Arylamine-substituted quinazolinone compounds useful as alpha 1A/B adrenergic receptor antagonists

ABSTRACT

Compounds represented by Formula I:  
                 
 
which are useful as are alpha-1A/B adrenoceptor antagonists, to methods of treating conditions associated with the activity of alpha-1A/B adrenoceptors, and to methods of making said compounds, wherein Ar, Z, R, R′, R 5  and R 10  are as defined herein.

CROSS REFERENCE TO PRIOR APPLICATION

This application claims benefit under Title 35 U.S.C. 119(e) of U.S.Provisional Application No. 60/484,570, filed Jul. 2, 2003, which ishereby incorporated by reference in its entirety

FIELD OF THE INVENTION

This invention relates to quinazolinone compounds, more particularly, to2-arylamine substituted quinazolinone compounds and salts thereof whichare useful as alpha-1-adrenergic receptor antagonists. The inventionfurther relates to pharmaceutical compositions containing saidcompounds, to methods for their use as therapeutic agents, and toprocesses for making said compounds.

BACKGROUND OF THE INVENTION

Alpha-1-adrenergic receptors are G-protein coupled transmembranereceptors that mediate various actions of the sympathetic nervous systemthrough the binding of the catecholamines, epinephrine, andnorepinephrine (NE). Currently, several subtypes of the alpha-1adrenergic receptors are known to exist for which the genes have beencloned: alpha-1A (previously known as alpha-1C), alpha-1B and alpha-1D.

Alpha-1 adrenoceptor antagonists have been shown in numerous clinicalstudies to be effective in relieving the symptoms associated with benignprostatic hypertrophy, also known as benign prostatic hyperplasia (BPH),an illness typically affecting men over fifty. The symptoms of thecondition include, but are not limited to, increased difficulty inurination and sexual dysfunction. Drugs such as prazosin, indoramin,doxazosin and tamsulosin are in common clinical use for BPH, and areeffective in reducing both “obstructive” symptoms (e.g. weak stream) and“irritative” symptoms (e.g. nocturia, urinary urge and frequency).However, these compounds are all non-subtype-selective and have thepotential to cause significant side-effects, particularly cardiovasculareffects such as postural hypotension, dizziness, and syncope, and CNSeffects such as aesthenia (tiredness). These effects can limit dosingand the clinical-efficacy in reducing symptoms associated with BPH.

Pharmacological studies resulting in the subdivision of alpha-1adrenoceptors into alpha-1A, alpha-1B, and alpha-1D adrenoceptors haveled to the suggestion that development of subtype-selective antagonistsmay allow for an improved symptomatic treatment of BPH with a lowerincidence of dose-limiting side-effects. Recently, much interest hasbeen focused on the role of the alpha-1A adrenoceptor subtype in BPH, asstudies have shown that this subtype predominates in the urethra andprostate of man and appears to be the receptor mediating NE-inducedsmooth muscle contraction in these tissues. See, e.g., Price et al., J.Urol. (1993), 150, at 546-551; Faure et al., Life Sci. (1994), 54 at1595-1605; Taniguchi et al., Naunyn Schmiedeberg's Arch. Pharmacol.(1997), 355 at 412-416, Forray et al., Mol. Pharmacol. (1994), 45 at703-708; Hatano et al., Br. J. Pharmacol. (1994), 113 at 723-728; andMarshall et al., Br J. Pharmacol. (1995), 115, at 781-786. Smooth muscletone is believed to contribute substantially to the total urinaryoutflow obstruction observed in patients with BPH [Furuya et al., J.Urol. (1982), 128 at 836-839]. Increased prostate mass is also acontributing factor. These observations have fuelled the hypothesis thatan alpha-1A subtype-selective antagonist may, via a selective andsignificant decrease in outlet resistance, lead to improvedpharmacotherapy for BPH.

However, in BPH, it is often the irritative symptoms which prompt thepatient to seek treatment, and these irritative symptoms may be presentin patients with no demonstrable obstruction (i.e. normal urine flowrates). Thus, it would be advantageous to provide a therapy for treatingpatients exhibiting obstructive symptoms and/or irritative symptoms. Itis believed that reduction of obstructive and irritative symptoms inpatients with BPH may be achieved via a combination of alpha-1A andalpha-1B subtype selectivity in a drug molecule. The lack of alpha-1Dadrenoceptor antagonism is expected to lead to reduced or fewer sideeffects than those associated with the use of non-subtype-selectiveagents.

The instant invention provides arylamine-substituted quinazolinonecompounds that are useful as alpha 1a/b adrenergic receptor antagonists.Certain arylamine quinazoline compounds useful for other purposes aredisclosed in Hess-et al., Anti-hypertensive2-Amino-4(3H)-quinazolinones, Medical Research Laboratories, Pfizer &Co. (January 1968); Klopman et al., Molecular Pharmacology, “AnArtificial Intelligence Approach to the Study of the Structural MoietiesRelevant to Drug-Receptor Interactions in Aldose Reductase Inhibitors,”Vol. 34, No. 6 (December 1988); DeRuiter et al., “Design and Synthesisof 2-(Arylamino)-4(3H)-quinazolinones as Novel Inhibitors of Rat LensAldose Reductase,” J. Med. Chem. Vol. 29 (1986), at pp. 627-29.

All publications, patents, and patent applications cited herein, whethersupra or infra, are each hereby incorporated by reference in itsentirety.

SUMMARY OF THE INVENTION

The present invention is directed to compounds useful as alpha 1A/Badrenergic receptor antagonists having the Formula (I),

wherein,

-   Y is optionally-substituted C₁₋₄alkylene, C₂₋₄alkenylene,    heterocyclylene, or heterocyclylC₁₋₄alkylene;-   Z is —(═O)— or —S(═O)₂—;-   R and R′ are alkyl;-   R⁵ is selected from hydrogen, halogen, cyano, hydroxy, —R⁶, and    —OR⁶;-   R⁶ is selected from alkyl, aryl, heteroaryl, cycloalkyl, and    heterocyclyl;-   R¹⁰ is selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl and    aralkyl;-   Ar is optionally-substituted aryl or heteroaryl, provided that if R⁵    is hydrogen, then Y—Ar considered together are not (i) unsubstituted    benzyl, (ii) benzyl having a para substituent selected from hydroxy    and CO₂H, or (iii) benzyl having a hydroxy meta substituent;    or an isomer or pharmaceutically-acceptable salt, hydrate, or    prodrug thereof.

The compounds of Formula (I) above are surprisingly advantageous inselectively antagonizing the alpha-1A and alpha-1B subtype receptorswith selectively lesser activity in antagonizing the alpha-1D adrenergicreceptor, particularly compounds where R⁵ is other than hydrogen.Accordingly, said compounds of Formula (I) are surprisingly advantageousin methods for treating diseases responsive to alpha-1A and alpha-1Breceptor antagonism with reduced side effects.

Another aspect of this invention relates to the methods of treating asubject having a disease state that is alleviated by treatment with analpha 1A/B adrenergic receptor antagonist, which comprises administeringto such a subject in need of treatment therefore, a therapeuticallyeffective amount of at least one compound of Formula I.

Still another aspect of the invention relates to a process for makingthe claimed compounds. In particular, the inventors herein havediscovered a process for making intermediate diones of the formula (II),

wherein R, R′ and R⁵ are as described above in the Summary of Invention,from nitrobenzoic acid compounds having the formula,

via reduction of the nitro group to an amino group in a water-basedsolvent, by addition of base, heterogenous catalyst, and exposure to ahydrogen atmosphere. This process is amendable to large-scale synthesisand is high-yielding and environmentally friendly.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. As used in the specification and the appended claims, thesingular forms “a”, “an,” and “the” include plural referents unless thecontext clearly dictates otherwise.

As used herein, the term “alkyl” means a linear or branched, saturatedmonovalent hydrocarbon moiety of one to eight carbon atoms (preferablyone to six carbon atoms), e.g., methyl, ethyl, n-propyl, 2-propyl,tert-butyl, pentyl, and the like. “Lower alkyl” means an alkyl of one tofour carbon atoms. When a subscript is used herein following a carbonatom, the subscript refers to the number of carbon atoms that the namedgroup may contain. Thus, for example, C₁₋₄alkyl means an alkyl of one tofour carbon atoms (i.e., lower alkyl) including methyl, ethyl, propyl,iso-propyl, butyl, and tert-butyl; hydroxy(C₁₋₄)alkyl means an alkyl ofone to four carbon atoms substituted with a hydroxy group;C₁₋₄alkoxyalkyl means an alkyl group substituted with an alkoxy groupwherein the alkoxy group has one to four carbon atoms;C₁₋₄alkoxy(C₁₋₄)alkyl means an alkyl group of one to four carbon atomssubstituted with an alkoxy group wherein the alkoxy group has one tofour carbon atoms; and so forth.

“Alkylene” means a linear or branched, saturated bivalent hydrocarbonmoiety of one to eight (preferably one to six) carbon atoms, e.g.,methylene, ethylene, propylene, and the like.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkylgroup, as defined above, being substituted with one or two (preferablyone) substituent(s) selected from the other, specifically-named group,also as defined herein. For example, “phenylalkyl” includes benzyl,phenylethyl, 2-phenylbutyl, and so forth. “Hydroxyalkyl” includes2-hydroxyethyl, 1-(hydroxymethyl)-2-methylpropyl, 3,4-dihydroxybutyl,and so forth. “Alkoxyalkyl” refers to an alkyl group substituted withone to two of OR′, wherein R′ is alkoxy as defined below.

The term “substituted alkyl” refers to an alkyl group as defined abovehaving one, two, three, or four substituents (preferably one to twosubstituents), independently selected from the group consisting of halo,haloalkoxy, trifluoromethyl, cyano, nitro, —OR^(a), —SR^(a), —S(O)R^(c),—S(O)₂R^(c), —C(═O)R^(a), —C(═O)NR^(a)R^(b), —C(O)₂R^(a),—C(O)₂NR^(a)R^(b), —S(O)₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)(C═O)R^(b),aryl, heteroaryl, cycloalkyl, and/or heterocyclo, wherein R^(a) andR^(b) are independently selected from hydrogen, C₁₋₆alkyl, aryl,heteroaryl, cycloalkyl, and heterocyclo, and R^(c)C is selected fromalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclo, and each of R^(a),R^(b), and R^(c)C in turn is optionally substituted with one, two, orthree of alkyl, halo, haloalkyl, OR^(e), haloalkoxy, cyano,—NR^(e)R^(f), —SO₂(alkyl), —CO₂R^(e), —C(═O)R^(e), and/or—NR^(e)C(═O)R^(f), and/or a C₁₋₆alkyl substituted with one to two ofhalo, OR^(e), haloalkoxy, cyano, —NR^(e)R^(f), —SO₂(alkyl), —CO₂R^(e),—C(═O)R^(e), and/or —NR^(e)C(═O)R^(f), wherein R^(e) and R^(f) areindependently selected from hydrogen, alkyl, aminoalkyl, hydroxyalkyl,alkoxyalkyl, cyanoalkyl, haloalkyl, and alkylaminoalkyl. Additionally,when a substituted alkyl group is substituted with a cyclic group suchas aryl, heteroaryl, cycloalkyl, or heterocyclo, it is understood saidcyclic group in turn may be substituted with one, two or three groupsselected from alkyl, halo, haloalkyl, OR^(e), haloalkoxy, cyano,—NR^(e)R^(f), —SO₂(alkyl), —CO₂R^(e), —C (═O)R^(e), and/or—NR^(e)C(═O)R^(f), and/or a C₁₋₆alkyl substituted with one to two ofhalo, OR^(e), haloalkoxy, cyano, —NR^(e)R^(f), —SO₂(alkyl), —CO₂R^(e),—C(═O) R^(e), and/or —NR^(e)C(═O)R^(f), wherein R^(e) and R^(f) are asdefined immediately above.

The term “substituted alkylene” means an alkylene group as defined abovewherein one, two or three carbon atoms of the alkylene straight orbranched chain is substituted with a group selected from those recitedabove for substituted alkyl groups.

The term “substituted lower alkyl” means an alkyl of one to four carbonatoms having one, two, or three substituents selected from those recitedabove for substituted alkyl.

The term “alkenyl” means a linear or branched, unsaturated monovalenthydrocarbon moiety of two to eight carbon atoms (preferably two to sixcarbon atoms), having at least one double bond, e.g., ethenyl, propenyl,butenyl, and the like. “Lower alkenyl” means an alkenyl of two to fourcarbon atoms.

“Alkenylene” means a linear or branched, unsaturated bivalenthydrocarbon moiety of two to eight (preferably two to six) carbon atoms,having at least one double bond, e.g., ethenylene, propenylene, and thelike.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having one, two, or three substituents, as valence permits(preferably one substituent), independently selected from the group ofsubstituents recited above for “substituted alkyl.” A “substitutedalkenylene” has one, two, or three substituents, as valence permits(preferably one substituent), independently selected from the group ofsubstituents recited for “substituted alkyl.”

“Alkoxy” refers to the group OR, wherein R is alkyl or substitutedalkyl. A “lower alkoxy” is a group —OR wherein R′ is C₁₋₄alkyl.

When the term “oxy” is used as a suffix following anotherspecifically-named group, as in “aryloxy”, “heteroaryloxy,” or“arylalkyloxy”, this means that an oxygen atom is present as a linker tothe other, specifically-named group. Thus, for example, “aryloxy” refersto the group —O—R, wherein R is aryl; “heteroaryloxy” refers to thegroup —O—R′, wherein R′ is heteroaryl; and “arylalkyloxy” refers to thegroup —O—R″, wherein R″ is arylalkyl such as benzyl. Similarly, a“substituted aryloxy” means the group —O—R, wherein R is substitutedaryl, and a “substituted heteroaryloxy” means the group —O—R′, whereinR′ is substituted heteroaryl.

“Amino” refers to the group NH₂. Thus, an aminoalkyl refers to an alkylgroup having an amino substituent, e.g., —CH₂—NH₂, —CH₂—CH₂—NH₂,—CH₂—CH(NH₂)—CH₃, and so forth.

“Alkylamino” as used herein refers to monoalkylamino groups having theformula —NHR, as well as dialkylamino groups having the formula —NRR′,wherein each R and R′ are selected from alkyl and substituted alkylgroups as defined above.

An “alkylaminoalkyl” refers to an alkyl group substituted by one to twoof —NHR and/or —NRR′, wherein each R and R′ is as defined above. A“lower alkylamino” refers to a group —NHR′ or —NR′R′, wherein each R′ isC₁₋₄alkyl.

“Aminoalkoxy” means a group —O—R—NHR′ or —O—R—NR′R″ wherein R isalkylene as defined herein and R′ and R″ each independently are alkyl asdefined herein.

As used herein, the term “alkoxyalkylamino” refers to the group—NR^(f)R^(g), wherein R^(f) is hydrogen, alkyl, or alkoxyalkyl, andR^(g) is an alkoxyalkyl (i.e., an alkyl group substituted with analkoxy).

“Alkoxyalkylaminoalkyl” refers to refers to an alkyl group as definedabove that is substituted with an alkoxyalkylamino group as definedabove.

A “hydroxyalkylamino” refers to the group —NR^(h)R^(i), wherein R^(h) ishydrogen, alkyl, or hydroxyalkyl, and R^(i) is hydroxyalkyl (i.e., analkyl group substituted with hydroxy).

“Hydroxyalkylaminoalkyl” refers to refers to an alkyl group as definedabove that is substituted with a hydroxyalkylamino group as definedabove.

“Aminoalkoxy” means a group —O—R—NHR′ or —O—R—NR′R″ wherein R isalkylene as defined above and R′ and R″ each independently are alkyl asdefined above.

The term “alkylsulfonyl” refers to the group —SO₂R′ wherein R′ is alkylor substituted alkyl, and “alkylsulfinyl” refers to the group —S(═O)R,wherein R is alkyl or substituted alkyl. Thus, accordingly,methylsulfonyl refers to —SO₂CH₃, and methylsulfinyl refers to the group—S(═O)CH₃.

“Alkylsulfonylalkyl” means an alkyl group as defined above substitutedwith an alkylsulfonyl group as defined herein.

“Alkylsulfonylaminoalkyl” means a group —R′—NR′-SO₂—R″ wherein R isalkylene as defined above and R′ and R′ each independently are alkyl asdefined herein.

“Acetamidinyl” means a group of the formula:

wherein each R is independently hydrogen or alkyl as defined herein.

“Alkoxyalkyl” means a group —R′—OR′ wherein R is alkylene as definedabove and R′ is alkyl as defined herein.

“Alkoxyalkoxy” means a group —O—R—OR′ wherein R is alkylene as definedabove and R′ is alkyl as defined herein.

The term “carboxy” refers to the group CO₂H. Thus, a carboxyalkyl is analkyl group as defined above having at least one substituent that is—CO₂H.

The term alkoxycarbonyl refers to the group —C(═O)R′, wherein R′ isalkoxy as defined above, i.e., alkoxycarbonyl is CO₂R, wherein R′ isalkyl or substituted alkyl, as defined above. A “lower alkoxycarbonyl”refers to the group CO₂R′, wherein R′ is lower alkyl. Thus, analkylalkoxycarbonyl is an alkyl group as defined above having at leastone substituent that is —CO₂R, wherein R′ is alkyl or substituted alkyl,as defined above.

“Alkoxyalkylaminocarbonyl” means a group —(C═O)—NR—R′—OR″ wherein R ishydrogen or alkyl as defined herein, R′ is alkylene as defined herein,and R″ is alkyl as defined herein.

“Hydroxyalkylaminocarbonyl” means a group —(C═O)—NR—R′—OH″ wherein R ishydrogen or alkyl as defined herein and R′ is alkylene as definedherein.

“Aminoalkylaminocarbonyl” means a group —(C═O)—NR—R′—NR″R″ wherein R ishydrogen or alkyl as defined herein, R′ is alkylene as defined herein,and each R″ independently is hydrogen or alkyl as defined herein.

“Heterocyclylalkylaminocarbonyl” means a group —(C═O)—NR—R′—R″ wherein Ris hydrogen or alkyl as defined herein, R′ is alkylene as definedherein, and R″ is heterocyclyl as defined herein.

The term alkylamidyl or alkylamide refers to the group —NH(C═O)R or—NR′(C═O)R, wherein R is alkyl or substituted alkyl, and R′ is loweralkyl. A lower alkylamidyl is a group —NH(C═O)R′ or —NR′(C═O)R′, whereR′ is lower alkyl.

The term “aryl” refers to a monovalent, monocyclic or bicyclic moiety inwhich at least one of the rings is an aromatic, carbocyclic moeity.Thus, the term “aryl” includes phenyl, 1-napthyl, and 2-napthyl. Theterm “aryl” also includes phenyl rings having fused thereto a secondnon-aromatic carbocyclic ring, or second fused heteroaryl orheterocyclic ring (thus, the term aryl includes groups such asbenzothienyl, benzopyrazolyl, benzopiperadinyl, benzocyclohexyl, and thelike), with the understanding, however, that in the case of bicyclicaryl groups, the point of attachment will be to the phenyl ring.

A “substituted aryl” is an aryl group as defined above having one tofour (preferably one to two) substituents independently selected fromthe group consisting of halo, haloalkyl, haloalkoxy, cyano, hydroxy,alkoxy, alkyl, substituted alkyl, —SO₂R^(r), —NR^(p)SO₂R^(r),—NR^(p)C(═O)R^(q), —NR^(p)R^(q), —C(═O)NR^(p)R^(q), —SO₂NR^(p)R^(q),—NR^(p)C(═NR^(s))R^(q), —N═C(R^(t))R^(u), —SO₂N═C(R^(t))R^(u),—C(═O)R^(p), —CO₂R^(p), and —OR^(p), heterocyclo, heteroaryl, phenyl andcycloalkyl, wherein each R^(r), R^(p), and R^(q) is selected fromhydrogen, alkyl, substituted alkyl, cycloalkyl, heterocyclo, aryl, andheteroaryl, except R^(r) is not hydrogen, R^(s) is selected fromhydrogen, alkyl, substituted alkyl, cycloalkyl, and heterocyclo, oralternatively, R^(p) and R^(q) when attached to the same nitrogen atommay be taken together to form a heterocyclo or heteroaryl; R^(t) isselected from hydrogen, alkyl, substituted alkyl, cycloalkyl, andheterocyclo, and R^(u) is amino or alkylamino, or alternatively, R^(t)and R^(u) are taken together to form a cycloalkyl or heterocyclo ring.It should be understood that when an aryl group is substituted by afurther ring, and/or when any of R^(p), R^(q), R^(r), R^(s), R^(t) andR^(u) are selected from and/or form a ring, said cyclic groups in turnare optionally substituted with one to three groups selected from alkyl,substituted alkyl, halogen, haloalkoxy, trifluoromethyl, cyano, nitro,—OR^(a), —SR^(a), —S(O)R^(c), —S(O)₂R^(c), —C(═O)R^(a),—C(═O)NR^(a)R^(b), —C(O)₂R^(a), —C(O)₂NR^(a)R^(b), —S(O)₂NR^(a)R^(b),—NR^(a)R^(b), and/or —NR^(a)(C═O)R^(b), wherein R^(a), R^(b) and R^(c)are as defined above in the definition of substituted alkyl groups.

The term “carbocyclic” means a cyclic moiety in which all ring atoms arecarbon atoms, including saturated, partially unsaturated, andunsaturated rings.

“Carbamylalkyl” means a group of the formula:

wherein each R is independently hydrogen or alkyl.

The term “cycloalkyl” as used herein refers to saturated or partiallyunsaturated, monovalent, monocyclic carbocyclic moieties of three toseven ring carbon atoms and further includes such rings having acarbon-carbon bridge of one, two, or three bridgehead carbon atoms,and/or having a second ring fused thereto, with the understanding thatthe point of attachment will be to the non-aromatic carbocyclic ringmoiety. Thus, the term “cycloalkyl” includes such rings as cyclopropyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like.Additionally, one or two carbon atoms of a cycloalkyl group mayoptionally contain a carbonyl oxygen group, e.g., one or two atoms inthe ring may be a moiety of the formula —C(═O)—.

A “substituted cycloalkyl” is a cycloalkyl group as defined above havingone to four (preferably one to two) substituents independently selectedfrom the group consisting of substituents recited above for substitutedaryl.

“Formamidinyl” means a group of the formula:

wherein R is hydrogen or alkyl as defined herein. The term “N,N-dimethylformamidine” or “N,N-dimethyl formamidinyl” refers to the above groupwherein R is methyl.

The term “halo,” “halide” or “halogen,” when referring to a substituentmeans fluoro, chloro, bromo, or iodo (preferably fluoro or chloro).

The term “haloalkyl” means alkyl substituted with one or more same ordifferent halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and thelike, and further includes those alkyl groups such as perfluoroalkyl inwhich all alkyl hydrogen atoms are replaced by fluorine atoms.

The term “haloalkoxy” means a haloalkyl group as defined above linkedthrough an oxygen atom, e.g., it includes —O—CH₂Cl, —O—CF₃, —O—CH₂CF₃,—O—CH₂CCl₃, and the like.

“Haloalkylamino” means a group —NH—R″ or —NR′—R″ wherein R′ is alkyl orhaloalkyl as defined herein and R″ is haloalkyl as defined herein.

“Haloalkylaminoalkyl” means a group —R′—NH—R″ or —NR′—R″ wherein R′ isalkylene as defined herein, R″ is alkyl or haloalkyl as defined hereinand R″ is haloalkyl as defined herein.

“Hydroxyalkyl” means a group —R′—OH wherein R is alkylene as definedherein.

“Hydroxyalkoxy” means a group —O—R′—OH wherein R is alkylene as definedherein.

“Heterocyclo,” “heterocyclyl,” or “heterocyclic” refers to a saturatedor partially-unsaturated non-aromatic monocyclic or bicyclic moiety inwhich one or two ring atoms are heteroatoms selected from N, O, orS(O)_(x) (where x is an integer from 0 to 2), the remaining ring atomsbeing carbon atoms, and additionally, one or two carbon atoms mayoptionally contain a carbonyl oxygen group, e.g., one or two atoms inthe ring may be a moiety of the formula —C(═O)—. Thus, the termheterocyclo includes rings such as tetrahydropyranyl, tetrahydrofuryl,piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, imidazolinyl, and the like, as well as such rings havinga carbonyl oxygen atom in the ring. In the case of a bicyclicheterocyclo, one of the two rings may be a carbocyclic ring with theunderstanding that in such cases the point of attachment will be to theheterocyclic ring.

“Heterocyclylalkylamino” means a group —NR—R′—R″ wherein R is hydrogenor alkyl as defined herein, R′ is alkylene as defined herein, and R″ isheterocyclyl as defined herein.

When reference is made to an imidazolinyl group, this is intended torefer to both

inclusive.

Imidazolinyl groups as defined herein may be optionally substituted withalkyl.

“Imidazolinylalkyl” means a group —R′—R′ wherein R is alkylene asdefined herein and R′ is imidazolinyl as defined herein.

A “substituted heterocyclo” or “substituted heterocycle” refers to aheterocyclo group as defined above having one to four substituents(preferably one to two substituents) selected from the group ofsubstituents recited above for substituted aryl.

A “heterocyclylene” means a bivalent heterocyclyl group as definedabove, i.e., a heterocyclyl attached to two other groups (e.g., —NR¹⁰and Ar in compounds of Formula I).

A “heterocyclylC₁₋₄alkylene” means a group X—R, wherein X is aheterocyclyl as defined above and R is a C₁₋₄alkylene as defined above.An optionally-substituted “heterocyclylc₁₋₄alkylene” means a group X—R,wherein X is an optionally-substituted heterocyclyl as defined hereinand R is an optionally substituted C₁₋₄alkylene as defined herein.

“Heteroaryl” means a monovalent, monocyclic aromatic moiety of 5 to 6ring atoms containing one, two, three, or four ring heteroatoms, eachindependently selected from N, O, or S, the remaining ring atoms beingcarbon, and it also includes such rings having a second ring fusedthereto of five to six ring atoms, wherein the second fused ring may bearomatic or nonaromatic and may be carbocyclic, heterocyclic, or aheteroaryl ring, with the understanding, however, that in such cases thepoint of attachment will be to an aromatic ring containing at least oneheteroatom. Thus, the term heteroaryl includes, but is not limited to,pyridyl, furyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl,imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuryl,isobenzofuryl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl,benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran, andbenzodiazepin-2-one-5-yl, and derivatives thereof.

A “substituted heteroaryl” is a heteroaryl ring as defined above havingone to four (preferably one or two) substituents selected from the groupof substituents recited above for substituted aryl.

“Optionally substituted pyrrolidinyl” means a group:

wherein E is —CH₂— or —(C═O)— and R is alkyl, alkoxy or hydroxy.

“Optionally substituted pyrrolidinylalkyl” means a group —R′—R′ whereinR is alkylene as defined herein and R′ is imidazolinyl as definedherein.

“Ureidylalkyl” means a group:

wherein each R is independently hydrogen or methyl.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry, i.e., an atom or a group capable of beingdisplaced by a nucleophile and includes halo (such as chloro, bromo, andiodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g.,acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

“Optional” or “optionally” means that the subsequently described eventmay but need not occur, and it includes instances where the event occursand instances in which it does not. For example, “optionally-substitutedcycloalkyl” refers to both cycloalkyl groups and substituted cycloalkylgroups, as defined above. When the term “optionally-substituted”precedes a number of different types of rings in one line or string,e.g., as in “optionally-substituted cycloalkyl or heterocyclo”, or“optionally-substituted carbocyclic or heterocyclic ring,” or“optionally-substituted aryl, heteroaryl, cycloalkyl, or heterocyclo,”it is intended that the term “optionally-substituted” modifies each ofthe rings identified in the line or string.

When the term “optionally-substituted” is used with respect to aparticularly-named cyclic group, such as “optionally-substitutedimidazolyl,” or “optionally-substituted imidazolidinyl,” it should beunderstood that the optional substituents for such particularly-namedrings may be selected from the group of substituents recited above withrespect to which the genus of which the particularly-named group is amember. Thus, for example, an “optionally-substituted imidazolyl” may bean unsubstituted imidazolyl or an imidazolyl group having one, two, orthree substituents selected from those recited above for substitutedheteroaryl groups. An optionally-substituted phenyl or benzyl ring willinclude an unsubstituted phenyl or benzyl group, and a phenyl or benzylgroup having substituents selected from those recited above forsubstituted aryl groups.

It should be understood that when reference is made to a specificheterocyclo or cycloalkyl group, such as cyclopentyl, pyrrolidinyl,pyrrolinyl, and imidazolinyl, such reference is intended to include suchrings wherein optionally one to two carbon atoms of the named ringcontain a carbonyl oxygen group, e.g., one or two atoms in the ring maybe a moiety of the formula —C(═O)—, as set forth above in the definitionof cycloalkyl and heterocyclo.

An optionally-substituted benzyl group means a benzyl group wherein thephenyl portion of the group is unsubstituted or substituted as definedabove in the definition for substituted aryl.

A benzyl group having a para substituent selected from hydroxy and CO₂H,means a group having the formula

wherein R is hydroxy or CO₂H, and benzyl having a hydroxy metasubstituent means a group having the formula,

When reference is made herein to substituents on the quinazolinone core,e.g., the “five position substituent,” the numbering of the ring atomsis intended to be as follows:

“Pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable. The termincludes excipients that are acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

“Pharmaceutically acceptable salt” of a compound means a salt that isgenerally safe, non-toxic and neither biologically nor otherwiseundesirable, and which possesses the desired pharmacological activity ofthe parent compound. Such salts include: (1) acid addition salts, formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic-acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; or (2) salts formed whenan acidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, and the like.

The terms “pro-drug” and “prodrug” are used interchangeably herein andrefer to any compound which releases an active parent drug according toFormula I in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of a compound of Formula I are prepared by modifyingone or more functional group(s) present in the compound of Formula I insuch a way that the modification(s) may be cleaved in vivo to releasethe parent compound. Prodrugs include compounds of Formula I wherein ahydroxy, amino, or sulfhydryl group in a compound of Formula I is bondedto any group that may be cleaved in vivo to regenerate the freehydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugsinclude, but are not limited to, esters (e.g. acetate,dialkylaminoacetates, formates, phosphates, sulfates and benzoatederivatives) and carbamates of hydroxy functional groups (e.g.N,N-dimethylcarbonyl), esters of carboxyl functional groups (e.g. ethylesters, morpholinoethanol esters), N-acyl derivatives (e.g. N-acetyl),N-Mannich bases, Schiff bases and enaminones of amino functional groups,oximes, acetals, ketals, and enol esters of ketones and aldehydefunctional groups in compounds of Formula I, and the like.

The prodrug can be metabolized before absorption, during absorption,after absorption, or at a specific site. Although metabolism occurs formany compounds primarily in the liver, almost all other tissues andorgans, especially the lung, are able to carry out varying degrees ofmetabolism. Prodrug forms of compounds may be utilized, for example, toimprove bioavailability, improve subject acceptability such as bymasking or reducing unpleasant characteristics such as bitter taste orgastrointestinal irritability, alter solubility such as for intravenoususe, provide for prolonged or sustained release or delivery, improveease of formulation, or provide site-specific delivery of the compound.Reference to a compound herein includes prodrug forms of a compound.Prodrugs are described in The Organic Chemistry of Drug Design and DrugAction, by Richard B. Silverman, Academic Press, San Diego (1992),Chapter 8: “Prodrugs and Drug delivery Systems” pp. 352-401; Design ofProdrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam (1985);Design of Biopharmaceutical Properties through Prodrugs and Analogs, Ed.by E. B. Roche, American Pharmaceutical Association, Washington (1977);and Drug Delivery Systems, ed. by R. L. Juliano, Oxford Univ. Press,Oxford (1980).

“Solvate” means solvent addition form that contains eitherstoichiometric or non-stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate.

“Protecting group” refers to an atom or group of atoms that is attachedto a reactive group in a molecule and masks, reduces, or prevents thereactivity of the group to which it is attached. Examples of protectinggroups can be found in Green and Wuts, Protective Groups in OrganicChemistry (Wiley, 2^(nd) ed. 1991), and Harrison and Harrison et al.,Compendium of Synthetic. Organic Methods, Vols. 1-8 (John Wiley andSons, 1971-1996). Representative amino protecting groups include formyl,acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ),tert-butoxycarbonyl (Boc), trimethyl silyl (TMS),2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), and the like. Representative hydroxyprotecting groups include those where the hydroxy group is eitheracylated or alkylated such as with benzyl or lower alkyl and tritylethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers, and allyl ethers.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers,” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, ifa carbon atom is bonded to four different groups, a pair of enantiomersis possible. An enantiomer can be characterized by the absoluteconfiguration of its asymmetric center and is described by the (R) and(S) sequencing rules of Cahn and Prelog, or by the manner in which themolecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either an individualenantiomer or as a mixture thereof. A mixture containing differentenantiomers is called a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures (racemic or otherwise) thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see March, Advanced Organic Chemistry, Chap. 4,4th edition, John Wiley and Sons, New York [1992]).

“Tautomers” refers to compounds whose structures differ markedly inarrangement of atoms, but which exist in easy and rapid equilibrium. Itis to be understood that compounds of Formula I may be depicted asdifferent tautomers. For example, compounds of Formula I wherein Z is—C(O)—, may be depicted in the following tautomer forms:

Compounds of Formula I may also contain other groups that exist intautomeric equilibrium. For example some of the compounds contain animidazolin-2-yl amino group which may be in equilibrium with animidazolin-2-ylidenamino group:

It should also be understood that when compounds have tautomeric forms,all tautomeric forms are intended to be within the scope of theinvention, and the naming of the compounds does not exclude any tautomerform.

“Treating” or “treatment” of a disease includes: (1) preventing thedisease, i.e., causing the clinical symptoms of the disease not todevelop in a mammal that may be exposed to or predisposed to the diseasebut does not yet experience or display symptoms of the disease; (2)inhibiting the progression of the disease, i.e., arresting or reducingthe development of the disease or its symptoms; and (3) relieving thedisease, i.e., causing regression of the disease or its symptoms.

“A therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect a treatment for the disease.

The “therapeutically effective amount” will vary depending on suchfactors as the compound being administered, the type of disease beingtreated, the progression or severity of the disease state, and the age,weight, and general health of the mammal being treated.

“Patient” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans, non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; and laboratory animals such as rats, mice, andguinea pigs. Examples of non-mammals include, but are not limited to,birds, reptiles, and the like.

“Pharmacological effect” as used herein encompasses effects produced inthe patient that achieve the intended purpose of a therapy. In onepreferred embodiment, a pharmacological effect means that primaryindications of the patient being treated are prevented, alleviated, orreduced. For example, a pharmacological effect would be one that resultsin the prevention, alleviation or reduction of primary indications in atreated patient. In another preferred embodiment, a pharmacologicaleffect means that disorders or symptoms of the primary indications ofthe patient being treated are prevented, alleviated, or reduced.

“Disease state” means any disease, condition, symptom, or indication.

“Disorders of the urinary tract” or “uropathy” refer to pathologicchanges in the urinary tract and symptoms thereof. Disorders of theurinary tract include overactive bladder (also known as detrusorhyperactivity), outlet obstruction, outlet insufficiency, pelvichypersensitivity, incontinence, benign prostatic hypertrophy orhyperplasia (BPH), prostatitis, detrusor hyperreflexia, urinaryfrequency, nocturia, urinary urgency, pelvic hypersensitivity, urgeincontinence, urethritis, prostatodynia, cystitis, and idiophaticbladder hypersensitivity.

“Overactive bladder” or “Detrusor hyperactivity” includes, but is notlimited to, changes symptomatically manifested as urgency, frequency,reduced bladder capacity, and incontinence episodes; changesurodynamically manifested as changes in bladder capacity, micturitionthreshold, unstable bladder contractions, and sphincteric spasticity;and symptoms usually manifested in detrusor hyperreflexia (neurogenicbladder), in conditions such as outlet obstruction, outletinsufficiency, pelvic hypersensitivity, or in idiopathic conditions suchas detrusor instability.

“Outlet obstruction” includes, but is not limited to, benign prostatichypertrophy or benign prostatic hyperplasia (BPH), urethral stricturedisease, tumors and the like. It is usually symptomatically manifestedas obstructive (low flow rates, difficulty in initiating urination, andthe like), or irritative (urgency, suprapubic pain, and the like).

“Outlet insufficiency” includes, but is not limited to, urethralhypermobility, intrinsic sphincteric deficiency, or mixed incontinence.It is usually symptomatically manifested as stress incontinence.

“Pelvic Hypersensitivity” includes but is not limited to, pelvic pain,interstitial (cell) cystitis, prostadynia, prostatitis, vulvadynia,urethritis, orchidalgia, and the like. It is symptomatically manifestedas pain, inflammation or discomfort referred to the pelvic region, andusually includes symptoms of overactive bladder.

“Sexual dysfunction” means the inability to achieve a normal sexualresponse and includes such conditions in males and females. Thus, itincludes male erectile dysfunction (MED) and female sexual dysfunction(FSD).

“Disease states associated with the Central Nervous System (CNS)” or“CNS disease states” mean neurological and/or psychiatric changes in theCNS, e.g., brain and spinal cord, which manifest in a variety ofsymptoms. Examples of CNS disease states include, but are not limitedto, migraine headache; cerebrovascular deficiency; psychoses includingparanoia, schizophrenia, attention deficiency, and autism;obsessive/compulsive disorders including anorexia and bulimia;posttraumatic stress disorders, sleep disorders, convulsive disordersincluding epilepsy and withdrawal from addictive substances; cognitivediseases including Parkinson's disease and dementia; andanxiety/depression disorders such as anticipatory anxiety (e.g., priorto surgery, dental work and the like), depression, mania, seasonalaffective disorder (SAD), and convulsions and anxiety caused bywithdrawal from addictive substances such as opiates, benzodiazepines,nicotine, alcohol, cocaine, and other substances of abuse; and improperthermoregulation.

PREFERRED EMBODIMENTS

The compounds of this invention demonstrate selectivity for thealpha-1A/B subtype over the alpha-1D subtype. The compounds of thisinvention may reduce both obstructive and irritative symptoms inpatients with BPH. The attenuated antagonism of alpha 1D-adrenoceptor isexpected to lead to reduced or fewer side effects than those associatedwith the use of non-subtype-selective agents. The compounds of theinvention are of the Formula (I)

wherein,

-   Y is optionally-substituted C₁₋₄alkylene, C₂₋₄alkenylene,    heterocyclylene, or heterocyclylC₁₋₄alkylene;-   Z is —C(═O)— or —S(═O)₂—;-   R and R′ are alkyl;-   R⁵ is selected from hydrogen, halogen, cyano, hydroxy, —R⁶, and    —OR⁶;-   R⁶ is selected from alkyl, aryl, heteroaryl, cycloalkyl, and    heterocyclyl;-   R¹⁰ is selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl and    aralkyl;-   Ar is optionally substituted aryl or heteroaryl, provided that if R⁵    is hydrogen, then Y—Ar considered together are not (i) unsubstituted    benzyl, (ii) benzyl having a para substituent selected from hydroxy    and CO₂H, or (iii) benzyl having a hydroxy meta substituent;    or an isomer or pharmaceutically-acceptable salt, hydrate, or    prodrug thereof.

Preferred compounds are those compounds having the Formula (Ia),

and isomers or pharmaceutically-acceptable salts, hydrates, or prodrugsthereof,wherein:

-   Y is —(CHR¹)— or —(CHR²—CHR³)—;-   R¹, R² and R³ are independently selected from hydrogen, lower alkyl,    and hydroxy, or R² and R³ may together form a bond so that Y is    ethenylene;-   R and R′ are lower alkyl;-   R⁵ is selected from halogen, cyano, hydroxy, —R⁶, and —OR⁶;-   R⁶ is selected from alkyl, aryl, heteroaryl, and cycloalkyl;-   R¹⁰ is selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl and    aralkyl; and    Ar is optionally-substituted aryl or heteroaryl.

In compounds of Formula (I) as set forth in the description and claimsherein, and in Formula (Ia) as set forth above, preferred compounds arethose in which R⁵ is not hydrogen. Even more preferred are compoundswhere R⁵ is selected from halogen, hydroxy, cyano, —R⁶, and —OR⁶,wherein R⁶ is selected from C₁₋₄alkyl, aminoalkyl,C₁₋₄alkylamino(C₁₋₄alkyl), hydroxyalkyl, alkoxyalkyl, phenoxyalkyl,benzyloxyalkyl, cycloalkylalkyl, phenyl, benzyl, and cycloalkyl, whereineach of said phenyl, benzyl, and cycloalkyl groups is optionallysubstituted with one to two of lower alkyl, substituted lower alkyl,cyano, and/or halogen. Even more preferred are compounds wherein R⁵ isselected from methyl, ethyl, n-propyl, isopropyl, cyano, halogen,methoxy, and ethoxy. Most preferred are compounds wherein R⁵ is methylor methoxy.

In compounds of Formulae (I) and (Ia), preferably R and R′ are both CH₃.

In compounds of Formulae (I) and (Ia), preferably R¹⁰ is selected fromhydrogen, alkyl, amino(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, and an optionally-substituted five or six memberedheterocyclo or C₃₋₇cycloalkyl. More preferred are compounds wherein R¹⁰is selected from hydrogen, lower alkyl, amino(C₁₋₄)alkyl,(C₁₋₄)alkylamino(C₁₋₂)alkyl, hydroxy(C₁₋₄)alkyl, and piperidinyloptionally-substituted with lower alkyl or benzyl. Even more preferredare compounds where R¹⁰ is selected from hydrogen, lower alkyl,hydroxymethyl, hydroxyethyl, —C₁₋₄alkylene-NH₂, —C₁₋₄alkylene-NH(CH₃),and/or —C₁₋₄alkylene-N(CH₃)₂, and most preferred are compounds whereinR¹⁰ is methyl or ethyl.

In certain embodiments of Formulae (I) and (Ia), Ar is phenylsubstituted with a group selected from:

a) optionally substituted alkenyl;

b) optionally-substituted alkyl having one two or three substituentsindependently selected from —NR^(d)(C═O)NR^(a)R^(b), —NR^(a)(C═O)OR^(c)and —NR^(a)S(O)₂R^(c) wherein R^(a), R^(b), and R^(d) are independentlyhydrogen, C₁₋₆alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclo, andR^(c)C is alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclo, and eachof R^(a), R^(b), R^(c), and R^(d) in turn is optionally substituted withone, two, or three of alkyl, halo, haloalkyl, OR^(e), haloalkoxy, cyano,—NR^(e)R^(f), —SO₂(alkyl), —CO₂R^(e), —C(═O)R^(f), and/or—NR^(e)C(═O)R^(f), and/or a C₁₋₆alkyl substituted with one to two ofhalo, OR^(e), haloalkoxy, cyano, —NR^(e)R^(f), —SO₂(alkyl), —CO₂R^(e),—C(═O)R^(e), and/or —NR^(c)C(═O)R^(f), wherein R^(e) and R^(f) areindependently hydrogen, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl,cyanoalkyl, haloalkyl, or alkylaminoalkyl; and

c) —NR^(j)S(O)₂NR^(p)R^(q), —NR^(j)C(═O)NR^(p)R^(q), —NR^(p)C(═O)OR^(r),—NR^(p)C(═O)C(═O)R^(q), and —NR^(j)C(═O)NR^(p)OR^(q) wherein each R^(j),R^(p)R^(q), and R^(r) is independently hydrogen, alkyl, substitutedalkyl, cycloalkyl, heterocyclo, aryl, or heteroaryl, except R^(r) is nothydrogen, or alternatively, R^(p) and R^(q) when attached to the samenitrogen atom may be taken together to form a heterocyclo or heteroaryl.It should be understood that when any of R^(j), R^(p), R^(q), and R^(r)is and/or forms a ring, said cyclic groups in turn are optionallysubstituted with one to three substituents selected from the groupconsisting of alkyl, substituted alkyl, halogen, haloalkoxy,trifluoromethyl, cyano, nitro, —OR^(a), —SR^(a), —S(O)R^(c),—S(O)₂R^(c), —C(═O)R^(a), —C(═O)NR^(a)R^(b), —C(O)₂R^(a),—S(O)₂NR^(a)R^(b), —NR^(a)R^(b), and —NR^(a)(C═O)R^(b).

In certain embodiments of Formulae (I) and (Ia), Ar is

and R⁷ may be selected from hydroxyalkoxy, optionally substitutedpyrrolodinyl, alkylaminoalkyl, alkylsulfonylaminoalkyl,haloalkylaminoalkyl, alkoxyalkylaminoalkyl, hydroxyalkylaminoalkyl,aminoalkoxy, aminoalkyl, ureidylalkyl, carbamylalkyl, acetamidinyl,formamidinyl, optionally substituted imidazolinyl, optionallysubstituted pyrrolodinylmethyl, optionally substitutedimidazolinylmethyl, alkoxyalkylaminocarbonyl, hydroxyalkylaminocarbonyl,aminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, andheterocyclylalkylamino.

In other embodiments of Formulae (I) and (Ia) where Ar is

R⁷ may be selected from methyl-(3,3,3-trifluoro-propyl)-amino-methyl-,2-hydroxy-3-methoxy-propoxy-, methoxy-,3-hydroxy-2-hydroxymethyl-propoxy-,1-(dimethylamino-carbonyl-methylamino)-ethyl-,1-[(methoxycarbonyl)-methylamino]-ethyl-,3-hydroxy-2-hydroxymethyl-propoxy-, 2,3-dihydroxypropoxy-,(S)-4-methoxy-2-oxo-pyrrolidin-1-yl-,2-methoxyethoxy-carbonylaminomethyl-,methanesulfonyl-N-methylamino-methyl-, 4,5-dihydro-oxazol-2-yl-,2-oxo-pyrrolidin-1-yl-, 2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy-,3-hydroxy-2-oxo-pyrrolidin-1-yl-, 2-methylamino-ethyl-,(S)-4-hydroxy-2-oxo-pyrrolidin-1-yl-,2-(N-ethyl-N-methyl-amino)-ethoxy-,1-(methanesulfonyl-N-methylamino)-ethyl-,2-(N-ethyl-N-methylamino)-ethyl-, 2-methylamino-ethoxy-,ethyl-(2-hydroxyethyl)-amino-methyl-, 2-hydroxy-ethoxy-,ethyl-(2-methoxyethyl)-aminomethyl-,2-hydroxy-ethyl-methylamino-methyl-, 3-methoxy-pyrrolidin-1-ylmethyl-,N-ethyl-N-methylamino-methyl-, 2-methoxyethyl-laminomethyl-,4-hydroxy-piperidin-1-ylmethyl-, hydroxy-pyrrolidin-1-ylmethyl-,aminomethyl-ethylamino-methyl-, 3-dimethylamino-propoxy-,pyrrolidin-1-ylmethyl-, azetidin-1-ylmethyl-,1,3-dimethyl-imidazolidin-2-ylideneamino)-,1-(methylamino-methyl-carbonyl-methylamino)-ethyl-,N,N-dimethylacetamidinyl-, 1-[(2-methoxyethyl)-methylamino]-ethyl-,methylamino-methyl-, dimethylamino-methyl-,3,4-dimethylimidazoline-2,4-dione-1-yl-,3-methylimidazoline-2,4-dione-1-yl)-, 1-dimethylamino-ethyl-,1-methylamino-ethyl-, cyclopropylamino-methyl-, isopropylamino-methyl-,N-methyl-N-propylamino-methyl-, methylamino-methyl-,N-ethyl-N-methyl-amino-methyl-, 3-methyl-2-oxo-pyrrolidin-1-yl-,2-oxo-imidazolidin-1-yl-, 2-methoxyethyl-amino-methyl-,1-methyl-piperidin-4-yl-, pyrrolidin-1-yl-, 4-methyl-piperazin-1-yl-,4-methyl-piperazin-1-yl-, N,N-dimethyl-formamidinyl)-, methyl-,4,5-dihydro-3H-pyrrol-2-ylamino-, acetamidinyl-,4,5-Dihydro-1H-imidazol-2-ylamino)-,4,4-dimethyl-4,5-dihydro-imidazol-1-yl)-, pyrimidin-2-ylamino-,(1H-Imidazol-2-ylmethyl)-amino-, amino-, cyano-, bromo-, fluoro,methylamino-, methylaminomethyl-, aminomethyl-, cyanomethyl-,hydroxymethyl-, morpholin-4-ylmethyl-, ethylaminomethyl-,(2,2,2-trifluoro-ethylamino)-methyl-,[(2-hydroxy-ethyl)-methylamino]-methyl-,[(2-methoxy-ethyl)-methylamino]-methyl-,[ethyl-(2-methoxy-ethyl)-amino]-methyl-,methoxymethylcarbonyl-N-methylaminomethyl-,1-methyl-4,5-dihydro-1H-imidazol-2-ylmethyl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-ylmethyl-,1-methyl-piperidin-4-ylmethyl-, methanesulfonyl-,dimethylaminosulfonyl-, 2-methoxyethylaminosulfonyl-,3-methoxypropylaminosulfonyl-, carboxy-, methyamino-carbonyl-,2-dimethylamino-ethyl)-aminocarbonyl-,2-dimethylaminoethyl-methylaminocarbonyl-,3-dimethylaminopropyl-ethylaminocarbonyl-, 2-hydroxyethylaminocarbonyl-,2-hydroxypropylaminocarbonyl-, 2-hydroxyethyl-methylaminocarbonyl-,2-methoxyethylaminocarbonyl-, 3-methoxypropylaminocarbonyl-,cyanomethylaminocarbonyl-, tetrahydrofuran-2-ylmethylaminocarbonyl-,furan-2-ylmethylaminocarbonyl-, (2-morpholin-4-yl)-ethylaminocarbonyl-,(4-hydroxymethyl)-piperidin-1-ylaminocarbonyl-, 2-hydroxyethoxy-,methanesulfinylmethoxy-, pyrimidin-2-yloxy-, hydroxy-,methanesulfonylmethoxy-, carboxymethoxy-, 2-methoxy-ethoxy-,3-methoxy-propyloxy-, 2-dimethylamino-ethoxy-, 2-ethylamino-ethoxy-,methanesulfonylamino-, dimethylaminosulfonylamino-,dimethylaminosulfonyl-N-methylamino-, methylcarbonylamino-, chloro-,dimethylaminocarbonylamino-, methoxycarbonylamino-,methoxycarbonyl-carbonyl-methylamino-, methoxyaminocarbonylamino-(183),2-hydroxyethyl-amino-, 3-hydroxypropyl-methylamino-,3-hydroxypropyl-amino-, 2-methoxyethyl)-amino-,2-methoxyethyl)-methylamino-, 3-hydroxypropyl)-methylamino-,(3-methoxypropyl)-amino-, 3-methoxypropyl)-methylamino-,bis-(2-hydroxyethyl)-amino-, (2-methylcarbonylamino)-ethylamino-,acetamidinyl-, N,N′-dimethylacetamidinyl-, N-methylacetamidinyl-,N,N-dimethylaminoformamidyl-, N,N-dimethylaminoisobutyramidinyl-,N,N-dimethylamino-(3-methoxy)-propionamidyl-,N,N-dimethylcyclobutane-carboxamidinyl-, imidazolidin-2-ylideneamino-,1-methyl-pyrrolidin-(2Z)-ylideneamino-,2-oxo-tetrahydro-furan-3-ylamino-,(4,5-Dihydro-3H-pyrrol-2-yl)-methyl-amino-,2-chloro-pyrimidin-4-ylamino-, 4-chloro-pyrimidin-2-ylamino-,2-chloro-5-methyl-pyrimidin-4-ylamino-, 2-oxo-pyrrolidin-1-yl-,1-methyl-4,5-dihydro-1H-imidazol-2-yl-,2-methyl-4,5-dihydro-imidazol-1-yl-,4,4-dimethyl-4,5-dihydro-imidazol-1-yl-,2,4,4-trimethyl-4,5-dihydro-imidazol-1-yl-, 4-methyl-imidazol-1-yl-,4-methyl-imidazol-1-yl-, 2-methyl-imidazol-1-yl-, pyrazol-1-yl-,3-methyl-pyrazol-1-yl-, 3,5-Dimethyl-pyrazol-1-yl-, pyrrolidin-2-yl-,pyrrolidin-3-yl-, 1-methyl-4,5-dihydro-1H-imidazol-2-yl-,1-ethyl-4,5-dihydro-1H-imidazol-2-yl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-yl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-yl-,1-(2-hydroxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl-,1-(2-methoxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl-, 1H-Imidazol-2-yl-,1-methyl-1H-imidazol-2-yl, 1-(2-hydroxy-ethyl)-1H-imidazol-2-yl-,1,1-Dioxo-1λ6-isothiazolidin-2-yl-, 2-oxo-oxazolidin-3-yl-,3-methyl-2-oxo-pyrrolidin-1-yl-, ethyl-2-oxo-pyrrolidin-1-yl)-,pyrrolidine-2,5-dione-1-yl-, 2-oxo-imidazolidin-1-yl-,3-methyl-2-oxo-imidazolidin-1-yl-, 3-ethyl-2-oxo-imidazolidin-1-yl-,3-(2-methoxy-ethyl)-2-oxo-imidazolidin-1-yl-, 1H-tetrazol-5-yl-,ethoxy-, 1-pyrrolidin-1-yl-ethyl-, 1-Azetidin-1-yl-ethyl-,aminosulfonyl-, N,N-dimethylamino-acetamidinesulfonyl-, and1-methanesulfonyl-methylamino)-ethyl-.

In still other embodiments of Formulae (I) and (Ia) where Ar is

R⁷ may be selected from:

wherein R³⁰ and R³¹ each independently is selected from hydrogen,methyl, ethyl, methoxyethyl and hydroxyethyl, and R³² is hydrogen,methyl or ethyl.

In yet other embodiments of Formulae (I) and (Ia) where Ar is

R⁷ may be selected from:

wherein:

each R³² independently is hydrogen or alkyl;

each R³³ independently is hydrogen, alkyl, hydroxy or alkoxy;

ehac R³⁴ independently is hydroxy or alkoxy; and

E is (C═O) or CH₂.

In certain embodiments of Formulae (I) and (Ia), Ar is

and R⁸ may be selected from hydroxyalkoxy, optionally substitutedpyrrolodinyl, alkylaminoalkyl, alkylsulfonylaminoalkyl,haloalkylaminoalkyl, alkoxyalkylaminoalkyl, hydroxyalkylaminoalkyl,aminoalkoxy, aminoalkyl, ureidylalkyl, carbamylalkyl, acetamidinyl,formamidinyl, optionally substituted imidazolinyl, optionallysubstituted pyrrolodinylmethyl, optionally substitutedimidazolinylmethyl, alkoxyalkylaminocarbonyl, hydroxyalkylaminocarbonyl,aminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, andheterocyclylalkylamino.

In other embodiments of Formulae (I) and (Ia) where Ar is

R⁸ may be selected from methyl-(3,3,3-trifluoro-propyl)-amino-methyl-,2-hydroxy-3-methoxy-propoxy-, methoxy-,3-hydroxy-2-hydroxymethyl-propoxy-,1-(dimethylamino-carbonyl-methylamino)-ethyl-,1-[(methoxycarbonyl)-methylamino]-ethyl-,3-hydroxy-2-hydroxymethyl-propoxy-, 2,3-dihydroxypropoxy-,(S)-4-methoxy-2-oxo-pyrrolidin-1-yl-,2-methoxyethoxy-carbonylaminomethyl-,methanesulfonyl-N-methylamino-methyl-, 4,5-dihydro-oxazol-2-yl-,2-oxo-pyrrolidin-1-yl-, 2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy-,3-hydroxy-2-oxo-pyrrolidin-1-yl-, 2-methylamino-ethyl-,(S)-4-hydroxy-2-oxo-pyrrolidin-1-yl-,2-(N-ethyl-N-methyl-amino)-ethoxy-,11-(methanesulfonyl-N-methylamino)-ethyl-,2-(N-ethyl-N-methylamino)-ethyl-, 2-methylamino-ethoxy-,ethyl-(2-hydroxyethyl)-amino-methyl-, 2-hydroxy-ethoxy-,ethyl-(2-methoxyethyl)-aminomethyl-,2-hydroxy-ethyl-methylamino-methyl-, 3-methoxy-pyrrolidin-1-ylmethyl-,N-ethyl-N-methylamino-methyl-, 2-methoxyethyl-laminomethyl-,4-hydroxy-piperidin-1-ylmethyl-, hydroxy-pyrrolidin-1-ylmethyl-,aminomethyl-ethylamino-methyl-, 3-dimethylamino-propoxy-,pyrrolidin-1-ylmethyl-, azetidin-1-ylmethyl-,1,3-dimethyl-imidazolidin-2-ylideneamino)-,1-(methylamino-methyl-carbonyl-methylamino)-ethyl-,N,N-dimethylacetamidinyl-, 1-[(2-methoxyethyl)-methylamino]-ethyl-,methylamino-methyl-, dimethylamino-methyl-,3,4-dimethylimidazoline-2,4-dione-1-yl-,3-methylimidazoline-2,4-dione-1-yl)-, 1-dimethylamino-ethyl-,1-methylamino-ethyl-, cyclopropylamino-methyl-, isopropylamino-methyl-,N-methyl-N-propylamino-methyl-, methylamino-methyl-,N-ethyl-N-methyl-amino-methyl-, 3-methyl-2-oxo-pyrrolidin-1-yl-,2-oxo-imidazolidin-1-yl-, 2-methoxyethyl-amino-methyl-,1-methyl-piperidin-4-yl-, pyrrolidin-1-yl-, 4-methyl-piperazin-1-yl-,4-methyl-piperazin-1-yl-, N,N-dimethyl-formamidinyl)-, methyl-,4,5-dihydro-3H-pyrrol-2-ylamino-, acetamidinyl-,4,5-Dihydro-1H-imidazol-2-ylamino)-,4,4-dimethyl-4,5-dihydro-imidazol-1-yl)-, pyrimidin-2-ylamino-,(1H-Imidazol-2-ylmethyl)-amino-, amino-, cyano-, bromo-, fluoro,methylamino-, methylaminomethyl-, aminomethyl-, cyanomethyl-,hydroxymethyl-, morpholin-4-ylmethyl-, ethylaminomethyl-,(2,2,2-trifluoro-ethylamino)-methyl-,[(2-hydroxy-ethyl)-methylamino]-methyl-,[(2-methoxy-ethyl)-methylamino]-methyl-,[ethyl-(2-methoxy-ethyl)-amino]-methyl-,methoxymethylcarbonyl-N-methylaminomethyl-,1-methyl-4,5-dihydro-1H-imidazol-2-ylmethyl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-ylmethyl-,1-methyl-piperidin-4-ylmethyl-, methanesulfonyl-,dimethylaminosulfonyl-, 2-methoxyethylaminosulfonyl-,3-methoxypropylaminosulfonyl-, carboxy-, methyamino-carbonyl-,2-dimethylamino-ethyl)-aminocarbonyl-,2-dimethylaminoethyl-methylaminocarbonyl-,3-dimethylaminopropyl-ethylaminocarbonyl-, 2-hydroxyethylaminocarbonyl-,2-hydroxypropylaminocarbonyl-, 2-hydroxyethyl-methylaminocarbonyl-,2-methoxyethylaminocarbonyl-, 3-methoxypropylaminocarbonyl-,cyanomethylaminocarbonyl-, tetrahydrofuran-2-ylmethylaminocarbonyl-,furan-2-ylmethylaminocarbonyl-, (2-morpholin-4-yl)-ethylaminocarbonyl-,(4-hydroxymethyl)-piperidin-1-ylaminocarbonyl-, 2-hydroxyethoxy-,methanesulfinylmethoxy-, pyrimidin-2-yloxy-, hydroxy-,methanesulfonylmethoxy-, carboxymethoxy-, 2-methoxy-ethoxy-,3-methoxy-propyloxy-, 2-dimethylamino-ethoxy-, 2-ethylamino-ethoxy-,methanesulfonylamino-, dimethylaminosulfonylamino-,dimethylaminosulfonyl-N-methylamino-, methylcarbonylamino-, chloro-,dimethylaminocarbonylamino-, methoxycarbonylamino-,methoxycarbonyl-carbonyl-methylamino-, methoxyaminocarbonylamino-(183),2-hydroxyethyl-amino-, 3-hydroxypropyl-methylamino-,3-hydroxypropyl-amino-, 2-methoxyethyl)-amino-,2-methoxyethyl)-methylamino-, 3-hydroxypropyl)-methylamino-,(3-methoxypropyl)-amino-, 3-methoxypropyl)-methylamino-,bis-(2-hydroxyethyl)-amino-, (2-methylcarbonylamino)-ethylamino-,acetamidinyl-, N,N′-dimethylacetamidinyl-, N-methylacetamidinyl-,N,N-dimethylaminoformamidyl-, N,N-dimethylaminoisobutyramidinyl-,N,N-dimethylamino-(3-methoxy)-propionamidyl-,N,N-dimethylcyclobutane-carboxamidinyl-, imidazolidin-2-ylideneamino-,1-methyl-pyrrolidin-(2Z)-ylideneamino-,2-oxo-tetrahydro-furan-3-ylamino-,(4,5-Dihydro-3H-pyrrol-2-yl)-methyl-amino-,2-chloro-pyrimidin-4-ylamino-, 4-chloro-pyrimidin-2-ylamino-,2-chloro-5-methyl-pyrimidin-4-ylamino-, 2-oxo-pyrrolidin-1-yl-,1-methyl-4,5-dihydro-1H-imidazol-2-yl-,2-methyl-4,5-dihydro-imidazol-1-yl-,4,4-dimethyl-4,5-dihydro-imidazol-1-yl-,2,4,4-trimethyl-4,5-dihydro-imidazol-1-yl-, 4-methyl-imidazol-1-yl-,4-methyl-imidazol-1-yl-, 2-methyl-imidazol-1-yl-, pyrazol-1-yl-,3-methyl-pyrazol-1-yl-, 3,5-Dimethyl-pyrazol-1-yl-, pyrrolidin-2-yl-,pyrrolidin-3-yl-, 1-methyl-4,5-dihydro-1H-imidazol-2-yl-,1-ethyl-4,5-dihydro-1H-imidazol-2-yl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-yl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-yl-,1-(2-hydroxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl-,1-(2-methoxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl-, 1H-Imidazol-2-yl-,1-methyl-1H-imidazol-2-yl, 1-(2-hydroxy-ethyl)-1H-imidazol-2-yl-,1,1-Dioxo-1λ6-isothiazolidin-2-yl-, 2-oxo-oxazolidin-3-yl-,3-methyl-2-oxo-pyrrolidin-1-yl-, ethyl-2-oxo-pyrrolidin-1-yl)-,pyrrolidine-2,5-dione-1-yl-, 2-oxo-imidazolidin-1-yl-,3-methyl-2-oxo-imidazolidin-1-yl-, 3-ethyl-2-oxo-imidazolidin-1-yl-,3-(2-methoxy-ethyl)-2-oxo-imidazolidin-1-yl-, 1H-tetrazol-5-yl-,ethoxy-, 1-pyrrolidin-1-yl-ethyl-, 1-Azetidin-1-yl-ethyl-,aminosulfonyl-, N,N-dimethylamino-acetamidinesulfonyl-, and1-methanesulfonyl-methylamino)-ethyl-.

In still other embodiments of Formulae (I) and (Ia) where Ar is

R⁸ may be selected from:

wherein R³⁰ and R³¹ each independently is selected from hydrogen,methyl, ethyl, methoxyethyl and hydroxyethyl, and R³² is hydrogen,methyl or ethyl.

In yet other embodiments of Formulae (I) and (Ia) where Ar is

R⁸ may be selected from:

wherein:

each R³² independently is hydrogen or alkyl;

each R³³ independently is hydrogen, alkyl, hydroxy or alkoxy;

ehac R³⁴ independently is hydroxy or alkoxy; and

E is (C═O) or CH₂.

In certain embodiments of Formulae (I) and (Ia), Y and Ar consideredtogether may be selected from one of (A), (B), (C), or (D):

wherein,

-   X is N or CH (wherein when X is CH, said hydrogen atom of X is    optionally replaced by a substituent R⁸);-   R¹, R² and R³ are individually independently selected from hydrogen,    lower alkyl, and hydroxy, or R² and R³ together form a bond to    define an ethylene group;-   R⁷ is selected from:    -   a) alkyl, halogen, and cyano;    -   b) alkyl substituted with one to two of halogen, hydroxy, cyano,        —NR^(12a)R^(14a), —NR^(12a)C(═O)R^(14a), azetidinyl,        morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl,        imidazolinyl, said rings in turn being optionally substituted        with one to two R²⁵;    -   c) —SO₂R¹¹, —NR¹²SO₂R¹¹, NR¹²CO₂R^(11a), —NR¹²C(═O)R^(11a),        —NR¹²R¹⁴, —C(═O)NR¹²R¹⁴, —SO₂NR¹²R¹⁴, NR¹²C(═NR¹³)R¹⁴,        —N═C(R¹⁵)R¹⁶, —SO₂N═C(R¹⁵)R¹⁶, —C(═O)R¹⁷, —CO₂R¹⁷, and —OR¹⁷;    -   d) heterocyclo or heteroaryl selected from pyrrolidin-2-yl,        pyrrolidin-3-yl, imidazolin-2-yl, imidazol-2-yl, piperidinyl,        and tetrazolyl, said heterocyclic and heteroaryl rings in turn        being optionally substituted as valance permits with one to        three of R²⁵;-   R⁸ is selected from alkyl, halogen, cyano, alkoxy, amino,    alkylamino, alkylsulfonyl, and piperidinyl, each of said R⁸ groups    in turn being optionally substituted with one to two of lower alkyl,    lower alkoxy, cyano, and/or halogen;-   R¹¹ is alkyl, alkylamino, aminoalkyl, or hydroxy(C₁₋₄)alkyl;-   R^(11a) is alkyl, alkylamino, aminoalkyl, —C(═O)alkyl, N(O)alkyl, or    hydroxy(C₁₋₄)alkyl;-   R^(12a) and R^(14a) are independently selected from hydrogen, alkyl,    hydroxyalkyl, lower alkoxyalkyl, haloalkyl, and lower    alkylamino(alkyl);-   R¹² and R¹³ are selected from hydrogen, alkyl, and    hydroxy(C₁₋₄)alkyl;-   R¹⁴ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, alkylaminoalkyl, alkylamidylalkyl, cyanoalkyl,    pyrrolidinyl, pyrrolinyl, imidazolinyl, pyrimidinyl,    tetrahydrofuranyl, furanylalkyl, isothiazolidinyl, oxazolindinyl,    tetrahydrofuranylalkyl, morpholinylalkyl, and imidazolylalkyl, said    R¹⁴ cyclic groups in turn being optionally substituted with one, two    or three groups where valence allows selected from R²⁵;-   or alternatively, R¹² and R¹⁴ when attached to the same nitrogen    atom (as in —NR¹²R¹⁴, C(═O)NR¹²R¹⁴, or —SO₂NR¹²R¹⁴), may be taken    together to form pyrrolidinyl, piperidinyl, imidazolinyl,    imidazolidinyl, pyrazolyl, or imidazolyl, said rings optionally    substituted where valence allows with one, two or three groups    selected from R²⁵;-   R¹⁵ is selected from hydrogen, alkyl, alkoxyalkyl, and    C₃₋₆cycloalkyl, and-   R¹⁶ is amino or alkylamino, or alternatively, R¹⁵ and R¹⁶ are taken    together to form a pyrrolidinyl or imidazolidinyl ring optionally    substituted with one, two, or three groups selected from R²⁵;-   R¹⁷ is selected from hydrogen, alkyl, methylsulfinylalkyl,    methylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl,    furanyl(C₁₋₄)alkyl, tetrahydrofuranyl(C₁₋₄)alkyl,    morpholinyl(C₁₋₄)alkyl, and pyrimidinyl, each R¹⁷ in turn being    optionally substituted where valence allows with one to two groups    selected from R²⁵;-   R²⁵ at each occurrence is selected independently of each other R²⁵    from lower alkyl, halogen, cyano, alkyl, hydroxy(C₁₋₄)alkyl,    (C₁₋₄)alkoxy(C₁₋₄)alkyl, halo(C₁₋₄)alkyl, cyano(C₁₋₄)alkyl,    amino(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₋₄)alkyl, halogen, haloalkoxy,    trifluoromethyl, cyano, nitro, —OR²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁶,    —C(═O)R²⁶, —C(—O)NR²⁶R²⁷, —C(O)₂R²⁶,    —C(O)₂NR²⁶R²⁷—S(O)₂NR²⁶R²⁷—NR²⁶R²⁷ and/or —NR²⁶(C═O)R²⁷, wherein R²⁶    and R²⁷ are selected from hydrogen and C₁₋₄alkyl, and R²⁸ is    C₁₋₄alkyl; and    m is 0, 1, or 2.

In certain preferred embodiments, Y and Ar considered together may beselected from one of (A) and (B);

-   R⁵ is selected from methyl, methoxy, cyano and fluoro; and-   R⁷ is selected from one of pyrrolidinyl, pyrrolinyl, imidazolinyl,    —NHC(═NH)R¹⁴, —N═C(H)(R¹⁶), —N═C(CH₃)(R¹⁶), —OR¹⁷, and C₁₋₂alkyl    optionally substituted with NR^(12a)R^(14a), wherein said    pyrrolidinyl, pyrrolinyl and imidazolinyl groups optionally may be    substituted with one to two of lower alkyl, hydroxy, lower alkoxy,    halogen, cyano, amino, (C₁₋₄)alkylamino, hydroxy(C₁₋₄)alkyl,    amino(C₁₋₄)alkyl, and/or (C₁₋₄)alkylamino(C₁₋₄)alkyl;-   R¹⁰ is methyl;-   R¹⁴ is C₃₋₆cycloalkyl or —C₁₋₂alkylene-(C₃₋₆cycloalkyl);-   R¹⁶ is —NH₂, —NH(C₁₋₂alkyl), or N(C₁₋₂alkyl)₂;-   R¹⁷ is —C₁₋₂alkylene-NH₂, —C₁₋₂alkylene-NH(lower alkyl), or    —C₁₋₂alkylene-N(lower alkyl)₂; and-   R^(12a) and R^(14a) are selected from hydrogen, lower alkyl,    hydroxy(C₁₋₄alkyl), and —C₁₋₄alkylene-O(lower alkyl); and    m is 0 or 1.

In certain embodiments of Formulae (I) and (Ia), Y and Ar consideredtogether may be

wherein:

-   R¹ is hydrogen, hydroxy, or lower alkyl; and-   R⁷ is selected from one pyrrolidinyl, pyrrolinyl, imidazolinyl,    —NR¹²R¹⁴, —NR¹²C(═NR¹³)R¹⁴, —N═C(R¹⁵)(R¹⁶), —OR¹⁷, and C₁₋₄alkyl    optionally substituted with pyrrolidinyl, pyrrolinyl, imidazolinyl,    —NR^(12a)R^(14a), and/or —OR^(17a), wherein said pyrrolidinyl,    pyrrolinyl and imidazolinyl groups in turn optionally may be    substituted with one to three groups selected from R²⁵;-   R^(12a), R^(14a), R¹⁷, and R^(17a) are independently selected from    hydrogen, lower alkyl, hydroxy(C₁₋₄alkyl), —C₁₋₄alkylene-O(lower    alkyl), —C₁₋₄alkylene-NH₂, —C₁₋₄alkylene-NH(lower alkyl),    —C₁₋₄alkylene-N(lower alkyl)₂, and —C₁₋₄alkylene-(C₃₋₆cycloalkyl);-   R¹² is hydrogen, alkyl, or hydroxy(C₁₋₄)alkyl;-   R¹⁴ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, alkylaminoalkyl, alkylamidylalkyl, cyanoalkyl,    pyrrolidinyl, pyrrolinyl, imidazolinyl, pyrimidinyl,    tetrahydrofuranyl, furanylalkyl, isothiazolidinyl, oxazolindinyl,    tetrahydrofuranylalkyl, morpholinylalkyl, and imidazolylalkyl, said    R¹⁴ cyclic groups in turn being optionally substituted with one, two    or three groups where valence allows selected from R²⁵;-   or alternatively, R¹² and R¹⁴ may be taken together to form    pyrrolidinyl, piperidinyl, imidazolinyl, imidazolidinyl, pyrazolyl,    or imidazolyl, said rings optionally substituted where valence    allows with one, two or three groups selected from R²⁵;-   R¹⁵ is independently selected from hydrogen, lower alkyl,    hydroxy(C₁₋₄)alkyl, and C₃₋₆cycloalkyl;-   R¹⁶ is independently amino or (C₁₋₄)alkylamino;-   or alternatively, R¹⁵ and R¹⁶ may be taken together to form a    pyrrolidinyl or imidazolinyl ring, wherein said pyrrolidinyl,    pyrrolinyl and imidazolinyl groups optionally may be substituted    with one to three groups selected from R²⁵; and-   R¹⁵ at each occurrence is independently selected from lower alkyl,    halogen, cyano, hydroxy(C₁₋₄)alkyl, and (C₁₋₄)alkoxy(C₁₋₄)alkyl.

In certain embodiments of Formulae (I) and (Ia), Ar is2,3-dihydro-1H-isoindol-5-yl optionally substituted at the 2-positionwith methyl or 2-methoxyethyl.

In certain embodiments of Formulae (I) and (Ia), Ar is 1H-indol-3-yl.

In certain embodiments of Formulae (I) and (Ia), Y is heterocyclylenesuch as piperazin-1,4-di-yl or piperidin-1-3-di-yl.

In certain embodiments of Formulae (I) and (Ia), Ar is pyridin 2-yloptionally substituted at the 4-position or 6-position withhydroxyalkoxy, optionally substituted pyrrolodinyl, alkylaminoalkyl,alkylsulfonylaminoalkyl, haloalkylaminoalkyl, alkoxyalkylaminoalkyl,hydroxyalkylaminoalkyl, aminoalkoxy, aminoalkyl, ureidylalkyl,carbamylalkyl, acetamidinyl, formamidinyl, optionally substitutedimidazolinyl, optionally substituted pyrrolodinylmethyl, optionallysubstituted imidazolinylmethyl, alkoxyalkylaminocarbonyl,hydroxyalkylaminocarbonyl, aminoalkylaminocarbonyl,heterocyclylalkylaminocarbonyl, or heterocyclylalkylamino.

According to another aspect of the invention, preferred compounds arethose compounds having the Formula (Ib),

and isomers or pharmaceutically-acceptable salts, hydrates, or prodrugsthereof, wherein: Y, R¹, R², R³, R, R′, R⁵, and R⁶ are as defined abovefor compounds of Formula (Ia);

-   X is N or CH (wherein when X is CH, said hydrogen atom of X is    optionally replaced by a substituent R⁸);-   R⁷ is selected from alkyl, substituted alkyl, halogen, cyano,    —SO₂R¹¹, —NR¹²SO₂R¹¹, NR¹²CO₂R^(11a), —NR¹²C(═O)R^(11a), —NR¹²R¹⁴,    —C(═O)NR¹²R¹⁴, —SO₂NR¹²R¹⁴, —NR¹²C(═NR¹³)R¹⁴, —N═C(R¹⁵)R¹⁶,    —SO₂N═C(R¹⁵)R¹⁶, —C(═O)R¹⁷, —CO₂R¹⁷, —OR¹⁷, heterocyclo, heteroaryl,    phenyl, and cycloalkyl, wherein said heterocyclo, heteroaryl,    phenyl, and cycloalkyl groups are optionally substituted with up to    three R²⁵;-   R⁸ is selected from alkyl, lower alkyl, halogen, cyano,    halo(C₁₋₄)alkyl, hydroxy, lower alkoxy, amino, (C₁₋₄)alkylamino,    (C₁₋₄)alkylamino(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkyl,    (C₁₋₄)alkoxy)(C₁₋₄)alkyl, pyrrolidinyl, and piperidinyl (said    pyrrolidinyl and piperidinyl in turn being optionally substituted    with one to two of lower alkyl, lower alkoxy, cyano, and/or    halogen);-   R¹⁰ is selected from hydrogen, C₁₋₄alkyl, hydroxy(C₁₋₄)alkyl, and    carboxy(C₁₋₄)alkyl;-   R¹¹, R¹², R¹³ and R¹⁵ are independently selected from hydrogen,    alkyl, hydroxyalkyl, alkoxyalkyl, and cycloalkyl, except R¹¹ is not    hydrogen;-   R^(11a) is selected from alkyl, alkylamino, aminoalkyl, —C(═O)alkyl,    N(O)alkyl, and hydroxyalkyl;-   R¹⁶ is independently amino or alkylamino; or alternatively, R¹⁵ and    R¹⁶ may be taken together to form a heterocyclo ring optionally    substituted with up to three groups selected from R²⁵;-   R¹⁴ and R¹⁷ are independently selected from hydrogen, alkyl,    substituted alkyl, and heterocyclo or heteroaryl optionally    substituted with up to three groups selected from R²⁵;-   or alternatively, R¹² and R¹⁴ when attached to the same nitrogen    atom (as in —NR¹²R¹⁴, C(═O)NR¹²R¹⁴, and —SO₂NR¹²R¹⁴), may be taken    together to form heterocyclo or heteroaryl ring optionally    substituted with up to three groups selected from R²⁵;-   R²⁵ is at each occurrence independently selected as valence permits    from alkyl, substituted alkyl, halogen, haloalkoxy, trifluoromethyl,    cyano, nitro, —OR²⁶, —SR²⁶, —S(O)R²⁶, —S(O)₂R²⁸, —C(═O)R²⁶,    —C(═O)NR²⁶R²⁷, —C(O)₂R²⁶, —C(O)₂NR²⁶R²⁷, —S(O)₂NR²⁶R²⁷, —NR²⁶R²⁷,    and/or —NR²⁶(C═O)R²⁷, wherein R²⁶ and R²⁷ are selected from    hydrogen, C₁₋₆alkyl, aryl, heteroaryl, cycloalkyl and heterocyclo,    and R²⁸ is selected from C₁₋₆alkyl, aryl, heteroaryl, cycloalkyl and    heterocyclo; and    m is 0, 1, or 2.

Even more preferred are compounds of Formula (Ib), as immediatelydefined above, in which X is CH, m is 0, and R⁷ is selected frompyrrolidinyl, pyrrolinyl, imidazolinyl, —NR¹²R¹⁴, —NR¹²C(═NR¹³)R¹⁴,—N═C(R¹⁵)(R¹⁶), —OR¹⁷, and C₁₋₄alkyl optionally substituted withpyrrolidinyl, pyrrolinyl, imidazolinyl, —NR^(12a)R^(14a), and/or—OR^(17a), wherein said pyrrolidinyl, pyrrolinyl and imidazolinyl groupsin turn optionally may be substituted with one to three of lower alkyl,halogen, cyano, and/or hydroxy(C₁₋₄)alkyl; R¹², R^(12a), R¹³, R¹⁴,R^(14a)R¹⁷, and R^(17a) are independently selected from hydrogen, loweralkyl, hydroxy(C₁₋₄alkyl), —C₁₋₄alkylene-O(lower alkyl),—C₁₋₄alkylene-NH₂, —C₁₋₄alkylene-NH(lower alkyl), —C₁₋₄alkylene-N(loweralkyl)₂, and —C₁₋₄alkylene-(C₃₋₆cycloalkyl); R¹⁵ is independentlyselected from hydrogen, lower alkyl, hydroxy(C₁₋₄)alkyl, andC₃₋₆cycloalkyl; R¹⁶ is independently amino or (C₁₋₄)alkylamino; oralternatively, R¹⁵ and R¹⁶ may be taken together to form a pyrrolidinyl,pyrrolinyl, or imidazolinyl ring, wherein said pyrrolidinyl, pyrrolinyland imidazolinyl groups optionally may be substituted with one to threeof lower alkyl, hydroxy, lower alkoxy, halogen, cyano, amino,(C₁₋₄)alkylamino, hydroxy(C₁₋₄)alkyl, amino(C₁₋₄)alkyl, and/or(C₁₋₄)alkylamino(C₁₋₄)alkyl.

In certain embodiments of Formula (Ib):

Y is methylene;

R and R′ are methyl;

R⁵ is methoxy or methyl;

one of R⁷ and R⁸ is hydrogen, or methoxy, and the other is selected frommethyl-(3,3,3-trifluoro-propyl)-amino-methyl-,2-hydroxy-3-methoxy-propoxy-, methoxy-,3-hydroxy-2-hydroxymethyl-propoxy-,1-(dimethylamino-carbonyl-methylamino)-ethyl-,1-[(methoxycarbonyl)-methylamino]-ethyl-,3-hydroxy-2-hydroxymethyl-propoxy-, 2,3-dihydroxypropoxy-,(S)-4-methoxy-2-oxo-pyrrolidin-1-yl-,2-methoxyethoxy-carbonylaminomethyl-,methanesulfonyl-N-methylamino-methyl-, 4,5-dihydro-oxazol-2-yl-,2-oxo-pyrrolidin-1-yl-, 2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy-,3-hydroxy-2-oxo-pyrrolidin-1-yl-, 2-methylamino-ethyl-,(S)-4-hydroxy-2-oxo-pyrrolidin-1-yl-,2-(N-ethyl-N-methyl-amino)-ethoxy-,1-(methanesulfonyl-N-methylamino)-ethyl-,2-(N-ethyl-N-methylamino)-ethyl-, 2-methylamino-ethoxy-,ethyl-(2-hydroxyethyl)-amino-methyl-, 2-hydroxy-ethoxy-,ethyl-(2-methoxyethyl)-aminomethyl-,2-hydroxy-ethyl-methylamino-methyl-, 3-methoxy-pyrrolidin-1-ylmethyl-,N-ethyl-N-methylamino-methyl-, 2-methoxyethyl-laminomethyl-,4-hydroxy-piperidin-1-ylmethyl-, hydroxy-pyrrolidin-1-ylmethyl-,aminomethyl-, ethylamino-methyl-, 3-dimethylamino-propoxy-,pyrrolidin-1-ylmethyl-, azetidin-1-ylmethyl-,1,3-dimethyl-imidazolidin-2-ylideneamino)-,1-(methylamino-methyl-carbonyl-methylamino)-ethyl-,N,N-dimethylacetamidinyl-, 1-[(2-methoxyethyl)-methylamino]-ethyl-,methylamino-methyl-, dimethylamino-methyl-,3,4-dimethylimidazoline-2,4-dione-1-yl-,3-methylimidazoline-2,4-dione-1-yl)-, 1-dimethylamino-ethyl-,1-methylamino-ethyl-, cyclopropylamino-methyl-, isopropylamino-methyl-,N-methyl-N-propylamino-methyl-, methylamino-methyl-,N-ethyl-N-methyl-amino-methyl-, 3-methyl-2-oxo-pyrrolidin-1-yl-,2-oxo-imidazolidin-1-yl-, 2-methoxyethyl-amino-methyl-,1-methyl-piperidin-4-yl-, pyrrolidin-1-yl-, 4-methyl-piperazin-1-yl-,4-methyl-piperazin-1-yl-, N,N-dimethyl-formamidinyl)-, methyl-,4,5-dihydro-3H-pyrrol-2-ylamino-, acetamidinyl-,4,5-Dihydro-1H-imidazol-2-ylamino)-,4,4-dimethyl-4,5-dihydro-imidazol-1-yl)-, pyrimidin-2-ylamino-,(1H-Imidazol-2-ylmethyl)-amino-, amino-, cyano-, bromo-, fluoro,methylamino-, methylaminomethyl-, aminomethyl-, cyanomethyl-,hydroxymethyl-, morpholin-4-ylmethyl-, ethylaminomethyl-,(2,2,2-trifluoro-ethylamino)-methyl-,[(2-hydroxy-ethyl)-methylamino]-methyl-,[(2-methoxy-ethyl)-methylamino]-methyl-,[ethyl-(2-methoxy-ethyl)-amino]-methyl-,methoxymethylcarbonyl-N-methylaminomethyl-,1-methyl-4,5-dihydro-1H-imidazol-2-ylmethyl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-ylmethyl-,1-methyl-piperidin-4-ylmethyl-, methanesulfonyl-,dimethylaminosulfonyl-, 2-methoxyethylaminosulfonyl-,3-methoxypropylaminosulfonyl-, carboxy-,methyamino-carbonyl-2-dimethylamino-ethyl)-aminocarbonyl-,2-dimethylaminoethyl-methylaminocarbonyl-,3-dimethylaminopropyl-ethylaminocarbonyl-, 2-hydroxyethylaminocarbonyl-,2-hydroxypropylaminocarbonyl-, 2-hydroxyethyl-methylaminocarbonyl-,2-methoxyethylaminocarbonyl-, 3-methoxypropylaminocarbonyl-,cyanomethylaminocarbonyl-, tetrahydrofuran-2-ylmethylaminocarbonyl-,furan-2-ylmethylaminocarbonyl-, (2-morpholin-4-yl)-ethylaminocarbonyl-,(4-hydroxymethyl)-piperidin-1-ylaminocarbonyl-, 2-hydroxyethoxy-,methanesulfinylmethoxy-, pyrimidin-2-yloxy-, hydroxy-,methanesulfonylmethoxy-, carboxymethoxy-, 2-methoxy-ethoxy-,3-methoxy-propyloxy-, 2-dimethylamino-ethoxy-, 2-ethylamino-ethoxy-,methanesulfonylamino-, dimethylaminosulfonylamino-,dimethylaminosulfonyl-N-methylamino-, methylcarbonylamino-, chloro-,dimethylaminocarbonylamino-, methoxycarbonylamino-,methoxycarbonyl-carbonyl-methylamino-, methoxyaminocarbonylamino-(183),2-hydroxyethyl-amino-, 3-hydroxypropyl-methylamino-,3-hydroxypropyl-amino-, 2-methoxyethyl)-amino-,2-methoxyethyl)-methylamino-, 3-hydroxypropyl)-methylamino-,(3-methoxypropyl)-amino-, 3-methoxypropyl)-methylamino-,bis-(2-hydroxyethyl)-amino-, (2-methylcarbonylamino)-ethylamino-,acetamidinyl-, N,N′-dimethylacetamidinyl-, N-methylacetamidinyl-,N,N-dimethylaminoformamidyl-, N,N-dimethylaminoisobutyramidinyl-,N,N-dimethylamino-(3-methoxy)-propionamidyl-,N,N-dimethylcyclobutane-carboxamidinyl-, imidazolidin-2-ylideneamino-,1-methyl-pyrrolidin-(2Z)-ylideneamino-,2-oxo-tetrahydro-furan-3-ylamino-,(4,5-Dihydro-3H-pyrrol-2-yl)-methyl-amino-,2-chloro-pyrimidin-4-ylamino-, 4-chloro-pyrimidin-2-ylamino-,2-chloro-5-methyl-pyrimidin-4-ylamino-, 2-oxo-pyrrolidin-1-yl-,1-methyl-4,5-dihydro-1H-imidazol-2-yl-,2-methyl-4,5-dihydro-imidazol-1-yl-,4,4-dimethyl-4,5-dihydro-imidazol-1-yl-,2,4,4-trimethyl-4,5-dihydro-imidazol-1-yl-, 4-methyl-imidazol-1-yl-,4-methyl-imidazol-1-yl-, 2-methyl-imidazol-1-yl-, pyrazol-1-yl-,3-methyl-pyrazol-1-yl-, 3,5-Dimethyl-pyrazol-1-yl-, pyrrolidin-2-yl-,pyrrolidin-3-yl-, 1-methyl-4,5-dihydro-1H-imidazol-2-yl-,1-ethyl-4,5-dihydro-1H-imidazol-2-yl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-yl-,1-isopropyl-4,5-dihydro-1H-imidazol-2-yl-,1-(2-hydroxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl-,1-(2-methoxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl-, 1H-Imidazol-2-yl-,1-methyl-1H-imidazol-2-yl, 1-(2-hydroxy-ethyl)-1H-imidazol-2-yl-,1,1-dioxo-1λ6-isothiazolidin-2-yl-, 2-oxo-oxazolidin-3-yl-,3-methyl-2-oxo-pyrrolidin-1-yl-, ethyl-2-oxo-pyrrolidin-1-yl)-,pyrrolidine-2,5-dione-1-yl-, 2-oxo-imidazolidin-1-yl-,3-methyl-2-oxo-imidazolidin-1-yl-, 3-ethyl-2-oxo-imidazolidin-1-yl-,3-(2-methoxy-ethyl)-2-oxo-imidazolidin-1-yl-, 1H-tetrazol-5-yl-,ethoxy-, 1-pyrrolidin-1-yl-ethyl-, 1-Azetidin-1-yl-ethyl-,aminosulfonyl-, N,N-dimethylamino-acetamidinesulfonyl-, and1-methanesulfonyl-methylamino)-ethyl-; and

R¹⁰ is hydrogen or methyl.

According to another aspect of the invention, preferred are thosecompounds having the Formula (Ic),

and isomers or pharmaceutically-acceptable salts, hydrates, or prodrugsthereof, wherein:

-   Y is —(CHR¹)— or —(CHR²—CHR³)—;-   R¹, R² and R³ are independently selected from hydrogen, lower alkyl,    and hydroxy;-   R⁵ is selected from C₁₋₄alkyl, halogen, cyano, hydroxy, C₁₋₄alkoxy,    —O(CH₂)_(r)NH₂, —O(CH₂)_(r)NH(C₁₋₄alkyl), —O(CH₂)_(r)N(C₁₋₄alkyl)₂,    —O(CH₂)_(r)OH, and —O(CH₂)_(r)O(C₁₋₄alkyl);-   R⁷ is selected from pyrrolidinyl, pyrrolinyl, imidazolinyl,    —NR¹²R¹⁴, —NR¹²C(═NR¹³)R¹⁴, —N═C(R¹⁵)(R¹⁶), —OR¹⁷, and C₁₋₄alkyl    optionally substituted with pyrrolidinyl, pyrrolinyl, imidazolinyl,    —NR^(12a)R^(14a), and/or —OR^(17a), wherein said pyrrolidinyl,    pyrrolinyl and imidazolinyl groups optionally may be substituted    with one to two of lower alkyl, hydroxy, lower alkoxy, halogen,    cyano, amino, (C₁₋₄)alkylamino, hydroxy(C₁₋₄)alkyl,    amino(C₁₋₄)alkyl, and/or (C₁₋₄)alkylamino(C₁₋₄)alkyl;-   R¹⁰ is methyl;-   R¹², R^(12a), R¹³, R¹⁴, R^(14a), R¹⁷, and R^(17a) are independently    selected from hydrogen, lower alkyl, hydroxy(C₁₋₄alkyl),    —C₁₋₄alkylene-O(lower alkyl), —C₁₋₄alkylene-NH₂,    —C₁₋₄alkylene-NH(lower alkyl), —C₁₋₄alkylene-N(lower alkyl)₂,    C₃₋₆cycloalkyl, and —C₁₋₄alkylene-(C₃₋₆cycloalkyl);-   R¹⁵ is hydrogen, lower alkyl, hydroxyC₁₋₄alkyl, or C₃₋₆cycloalkyl;-   R¹⁶ is independently amino or (C₁₋₄)alkylamino;-   or alternatively, R¹⁵ and R¹⁶ may be taken together to form a    pyrrolidinyl, pyrrolinyl, or imidazolinyl ring, wherein said    pyrrolidinyl, pyrrolinyl and imidazolinyl groups optionally may be    substituted with one to three of lower alkyl, halogen, cyano,    —C(═O)H, —C(═O)(C₁₋₄)alkyl, amino, (C₁₋₄)alkylamino,    hydroxy(C₁₋₄)alkyl, amino(C₁₋₄)alkyl, and    (C₁₋₄)alkylamino(C₁₋₄)alkyl; and    r is 1, 2, 3, or 4.

Within the above group of compounds according to Formula (Ic), morepreferred are compounds having the Formula (Id),

wherein R⁵ is selected from methyl, methoxy, cyano and fluoro; and

-   R⁷ is selected from one of pyrrolidinyl, pyrrolinyl, imidazolinyl,    —NHC(═NH)R¹⁴, —N═C(H)(R⁶), —N═C(CH₃)(R¹⁶), —OR¹⁷, and C₁₋₂alkyl    optionally substituted with —NR^(12a)R^(14a), wherein said    pyrrolidinyl, pyrrolinyl and imidazolinyl groups optionally may be    substituted with one to two of lower alkyl, hydroxy, lower alkoxy,    halogen, cyano, amino, (C₁₋₄)alkylamino, hydroxy(C₁₋₄)alkyl,    amino(C₁₋₄)alkyl, and/or (C₁₋₄)alkylamino(C₁₋₄)alkyl;-   R¹⁴ is C₃₋₆cycloalkyl or —C₁₋₂alkylene-(C₃₋₆cycloalkyl);-   R¹⁶ is —NH₂, —NH(C₁₋₂₂alkyl), or N(C₁₋₂alkyl)₂;-   R¹⁷ is —C₁₋₂alkylene-NH₂, —C₁₋₂alkylene-NH(lower alkyl), or    —C₁₋₂alkylene-N(lower alkyl)₂; and-   R^(12a) and R^(14a) are selected from hydrogen, lower alkyl,    hydroxy(C₁₋₄alkyl), and —C₁₋₄alkylene-O(lower alkyl).

Within the above group of preferred compounds, more preferred are thosecompounds as immediately defined above wherein R⁷ is selected from oneof:

wherein R³⁰, R³¹, and R³² are independently selected from hydrogen andmethyl.

According to another aspect of the invention, combinations of thepreferred groups described herein form other preferred embodiments. Inthis manner, a variety of preferred compounds are embodied within thepresent invention. For example, another group of preferred compounds,selected from a combination of preferred groups recited above, are thosecompounds having the formula (Ic), as immediately defined above, whereinR⁵ is fluoro, cyano, methyl, or methoxy, and R¹⁰ is methyl. Thus,further combinations of preferred compounds may be selected from thepreferred groups recited above.

Among other discoveries, the inventors herein have discovered that a5-position substituent on the quinazolinone core produces an unexpectedand/or surprising advantage with regard to the compounds' effectivenessas selective antagonists of the alpha-1A and alpha-1B adrenoceptors. The5-position substituent advantageously affects the metabolic pathway forthe claimed quinazolinone compounds and increases their bioavailability,thus enhancing their pharmacological effects.

Utility

Alpha-1 adrenoceptors mediate the contractile state of smooth muscletissue and are present in the human prostate, bladder neck and urethra.Alpha-1 adrenoceptor stimulation also produces contraction of urethraland bladder neck smooth muscle, leading to increased resistance inurinary outflow. Thus, alpha-1 adrenoceptor antagonists may be useful intreating disorders of the urinary tract, as previously defined.

Alpha-1B adrenoceptors are present in the liver, heart and cerebralcortex and are believed to be involved in mediating vascular contractileand blood pressure responses. Alpha-1B adrenoceptors are also present inareas of the spinal cord which receive input from sympathetic neuronsoriginating in the pontine micturition center and are presumed to beinvolved in the regulation of bladder function. Additionally, alpha-1Badrenoceptor antagonists are useful as analgesic/antihyperalgesictherapies for treating pain, including symptoms of acute pain,inflammatory pain, neuropathic pain (including thermal and mechanicalhyperalgesia as well as thermal and mechanical allodynia), complexregional pain syndromes (including reflex sympathetic dystrophy,causalgia and sympathetically maintained pain and the like).

However, it must be noted that in BPH, it is often the irritativesymptoms which prompt the patient to seek treatment, and that theseirritative symptoms may be present even in patients with no demonstrableobstruction (i.e. normal urine flow rates). By combining both alpha-1Aand alpha-1B subtype selectivity in a compound, a reduction of bothobstructive and irritative symptoms in patients with BPH may beachieved. Lower levels or lack of alpha-1D adrenoceptor antagonismshould lead to reduced or fewer side effects than those associated withthe use of non-subtype-selective agents.

In a preferred embodiment, the compounds of this invention are usefulfor treating disorders and symptoms which can be ameliorated by blockadeof alpha1A/B adrenoceptors, such as reduction or alleviation of urinarytract disorders, for example, pelvic hypersensitivity (includinginterstitial cystitis, prostatitis, pelvic pain syndrome, infectiouscystitis, prostatodynia, and the like), overactive bladder, urinaryfrequency, nocturia, urinary urgency, detrusor hyperreflexia, outletobstruction, BPH, prostatitis, urge incontinence, urethritis, idiophaticbladder hypersensitivity, sexual dysfunction, and the like.

In another preferred embodiment, the compounds of this invention areuseful for treating disorders and symptoms which can be ameliorated byblockade of alpha-1A/B adrenoceptors, such as reduction or alleviationof pain disorders, for example inflammatory pain, neuropathic pain,cancer pain, acute pain, chronic pain or complex regional painsyndromes.

In a more preferred embodiment, the compounds of this invention areuseful for treating disorders and symptoms which can be ameliorated byblockade of both alpha-1A and alpha-1B adrenoceptors with diminishedblockade of alpha-1D adrenoceptors, such as reduction or alleviation ofboth outlet obstruction, such as benign prostatic hypertrophy, andirritative symptoms associated with it, such as pain.

In another preferred embodiment, the compounds of this invention areuseful for the improvement of sexual dysfunction including male erectiledysfunction (MED) and female sexual dysfunction (FSD).

These and other therapeutic uses are described, for example, in Goodman& Gilman's, The Pharmacological Basis of Therapeutics, ninth edition,McGraw-Hill, New York, 1996, Chapter 26, 601-616; and Coleman, R. A.,Pharmacological Reviews, 1994, 46, 205-229.

Administration and Pharmaceutical Composition

The present invention includes pharmaceutical compositions comprising atleast one compound of the present invention, or an individual isomer,racemic or non-racemic mixture of isomers or a pharmaceuticallyacceptable salt or solvate thereof, together with at least onepharmaceutically acceptable carrier, and optionally other therapeuticand/or prophylactic ingredients.

In general, the compounds of the present invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

In general, compounds of the present invention will be administered aspharmaceutical formulations including those suitable for oral (includingbuccal and sublingual), rectal, nasal, topical, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or pulmonary in a form suitable foradministration by inhalation or insufflation. The preferred manner ofadministration is generally oral using a convenient daily dosage regimenwhich can be adjusted according to the degree of affliction.

A compound or compounds of the present invention, together with one ormore conventional adjuvants, carriers, or diluents, may be placed intothe form of pharmaceutical compositions and unit dosages. Thepharmaceutical compositions and unit dosage forms may be comprised ofconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and the unit dosage forms maycontain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed. Thepharmaceutical compositions may be employed as solids, such as tabletsor filled capsules, semisolids, powders, sustained release formulations,or liquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) to about 20milligram of active ingredient or, more broadly, about 0.01 to about onehundred (100) milligrams, per tablet, are accordingly suitablerepresentative unit dosage forms.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms. The pharmaceuticalcompositions and dosage forms may comprise a compound or compounds ofthe present invention or pharmaceutically acceptable salts thereof asthe active component. The pharmaceutically acceptable carriers may beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier may be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier, providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is in association with it. Similarly,cachets and lozenges are included. Tablets, powders, capsules, pills,cachets, and lozenges may be as solid forms suitable for oraladministration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays may contain in addition to the active ingredient, such carriersas are known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the case of a dropper or pipette, dosing may be achieved by thepatient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example on the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, and starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidine (PVP). The powder carrier will forma gel in the nasal cavity. The powder composition may be presented inunit dose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described in Examples below.

Abbreviations

Throughout the disclosure, and in the following Schemes and Examplesherein, the following abbreviations are used for ease of reference:

BOC tert-butoxycarbonyl

BPH Benign prostatic hypertrophy or benign prostatic hyperplasia

CBZ carbobenzyloxy

CNS Central nervous system

DCM dichloromethane

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EtOH ethanol

EtOAc Ethyl Acetate

Hal Halogen or halide

KOH Potassium hydroxide

L Leaving group

MeOH methanol

P Protective group

Pd/C Palladium on carbon

THF Tetrahydrofuran

General Synthetic Schemes

Compounds of the present invention may be made by the methods depictedin the illustrative synthetic reaction schemes shown and describedbelow.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention may be synthesized, andvarious modifications to these synthetic reaction schemes may be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes may be isolated and purified if desired using conventionaltechniques including but not limited to filtration, distillation,crystallization, chromatography, and the like. Such materials may becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably take place at atmospheric pressure over a temperature rangefrom about −78° C. to about 150° C., more preferably from about 0° C. toreflux, and most preferably and conveniently at about room (or ambient)temperature, e.g., about 20° C.

Compounds of formula (Ia) can be prepared by coupling2-chloro-quinazoline-4-one compounds (1) with amine compounds (2), in asolvent such as EtOH, with or without additives such asdiisopropylethylamine. Quinazolin-4-ones can be prepared as described inCronin et al., J. Med. Chem, Vol. 11 (1968), at pp. 130-136, and WO02/053558 A1, which are incorporated herein by reference. Alternatively,2-chloro-quinazoline-4-one compounds (1) can be prepared as describedbelow using the method described in Scheme 3.

Compounds of formula (Ie), (If), and (Ig) can be prepared from2-chloro-quinazoline-4 one compounds (4) using the process shown inScheme 2.

Compounds of formula (Ie), (If), and (Ig) can be also prepared from2-chloro-quinazoline compounds (1) using the process shown in Scheme 2.

2-Chloro-quinazolin-4-one compounds (1) can be converted to compounds offormula (1e) by combining amines such as (3)(or a suitable salt of suchamines, e.g. HCl salt thereof) with compounds (1) in a solvent, such asisopropanol, and heating the reaction mixture in the presence or absenceof an additive like diisopropylethylamine. Compounds (1e) can beisolated by cooling and filtering the reaction mixture. In some cases,the recovery of product can be increased by adding an anti-solvent (e.g.water) prior to performing the filtration.

Compounds of formula (1f) can be prepared by combining compounds (1e), aheterogenous catalyst on an inert support (e.g. palladium on carbon), anorganic solvent (e.g. ethanol), water, and base (e.g. NaOH). Then, tothis reaction mixture, hydrogen is introduced either directly orindirectly (e.g., via transfer hydrogenation using formate salts,hydrazine, etc.), and the nitro group is reduced to an amino group. Thecatalyst and support are removed, and the reaction mixture isneutralized by addition of acid (eg. acetic, trifluoroacetic,hydrochloric acid, etc). The precipitated compound of formula (1f) isthen collected via filtration.

Compounds of formula (1g) can be prepared by combining compounds offormula (1f) in an organic solvent (methylene chloride, acetonitrile,etc) and a solution of iminium salt (4) (prepared by activation of theappropriate acetamide or formamide with phosphorous oxychloride ortrifluoromethanesulfonic anhydride as described by Fabio et al, J. Med.Chem., Vol. 21, 273-276 (1978); Campbell et al, Tetrahedron Letters, Vol25, 4813-4816 (1984), and Sforza et al, Tetrahedron Letters, Vol 39,711-714 (1998).) The reaction is quenched by the addition of water,cooled, and then the pH is adjusted to ˜8.5 with a base (e.g. NaOH, KOH,etc). The aqueous layer is extracted with an organic solvent (e.g.methylene chloride), then the organic solvent is converted to an alcohol(e.g. isopropanol), heated, cooled then filtered to provide compounds offormula (Ig).

Quinazolin-4-ones (1) can be prepared as described in Cronin et al. orWO 02/053558 A1, cited above, or using the method described in Scheme 3.

Scheme 3 illustrates an alternate method for making2-chloro-quinazolin-4-one compounds (1), used as starting material inSchemes 1 and 2.

Dione intermediate (5) is converted to dichloroquinazoline (6) bycombining (5) with a chlorinating and dehydrating agent (e.g.,phosphorous oxychloride) in an organic solvent (e.g. acetonitrile) andheating the reaction mixture. The dichloroquinazoline (6) is isolated byquenching the reaction mixture into water and filtering the precipitatedproduct, or by quenching the reaction mixture into a mixture of waterand a water-immiscible solvent (e.g. methylene chloride), and extractingthe product into the organic solvent. The solvent is evaporated toprovide compound (6).

Compound (6) is then combined with a base (e.g., KOH, NaOH) in a mixtureof water and a solvent like THF. At the end of the reaction, the organicsolvent is partially removed by distillation, an acid (e.g. HOAc) isadded, and the compound (1) is collected via filtration. Dioneintermediates (5) are commercially available or can be readily preparedby one skilled in the field, e.g., as described in Mizuno et al.,Heteroatom Chemistry, Vol. 11(6) (2000), at pp. 428-433; Mizuno et al.,Tetrahedron Letters, Vol. 41 (7) (2000), at pp. 1051-51; U.S. Pat. No.6,376,667-B1; U.S. Pat. No. 6,048,864; WO 97/23462; EP Pat. 775697-A1;and so forth.

Alternatively, dione intermediates (5) may be prepared as described inScheme 4.

Scheme 4 illustrates an alternative method for making of diones (5),used in Scheme 3 to prepare 2-chloro-quinazolin-4-one compounds (1).

Nitro-acids (8) are commercially available, or can be readily preparedby one skilled in the field from carboxylic acids (7) using severalmethods, including that of Kowalczyk et al., Organic Process Researchand Development, Vol. 1 (1997), at pp. 355-358. Carboxylic acids (7) arecommercially available.

Nitro acids (8) are dissolved in water by addition of base (e.g., NaOH,KOH, LiOH). Typically, the amount of base used to dissolve the acids isin the range of a 1.3 to 1.5 molar equivalent, e.g., at a pH≧12. Aheterogenous catalyst on an inert support is added (e.g., palladium oncarbon), and the reaction mixture is exposed to a hydrogen atmosphereeither directly (hydrogen gas) or indirectly (via transfer hydrogenationtechnique using, e.g., formate salts, hydrazine, etc., as the hydrogensource). The nitro-group is thereby converted to an amino group toprovide compounds (9).

Compounds (9) can be converted to urea (10) by addition of a cyanatesalt (e.g., KOCN, NaOCN) and an acid (e.g., HCl, HOAc). For thisurea-forming step, the pH is preferably maintained in the range of 6.0to 8.0, more preferably between 6.8 and 8.0. At pH greater than 8, theurea formation step may slow down, and when the pH is between 5.6 and6.0, an undesirable side reaction may occur. Degradation occurs at lowerpH, e.g., at pH of ˜3.9. The urea (10) is then cyclized to a dionederivative (5) by adding a base (e.g., NaOH, KOH), wherein the pH istypically maintained at ≧12, and heating the reaction mixture. Theresults of this cyclization step may be improved as the pH is increased.The dione (5) is precipitated by adding an acid (e.g., HCl, HOAc) to thereaction mixture, to achieve a pH of about less than 8.2, morepreferably in the range of 6.5 to 7.5, and the dione (5) may be isolatedsuch as by filtration. Other acids also may be used, e.g., any acid thatwill generate HOCN in-situ from the cyanate salt and the acid.

The process of Scheme 4 is particularly advantageous in that thewater-insoluble compounds (8)-(5) are converted into water-solublecompounds by conversion to their respective salts (by addition of base)and then the pH is adjusted to allow the desired reaction to occur in awater-based solvent system.

EXAMPLES

The following preparations and examples are provided to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. However, these Examples should not be considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

Example A-16,7-Dimethoxy-2-[methyl-(3-pyrrolidin-1-yl-benzyl)-amino]-1H-quinazolin-4-one

Step 1

Benzylamine (1) was prepared following the procedure of Sznaidman etal., Bioorg. Med. Chem. Lett., 6(5) (1996), at pp. 565-568.

Step 3

Benzylamine (1) (4.8 g, 27.3 mmol) in 100 mL DCM was reacted with 6.1 g(28 mmol) of di-tert-butyl dicarbonate for 2 h. The solvent wasevaporated under reduced pressure and the remaining solid was dried at60° C. in vacuo to afford 7.7 g of the carbamate (2) (Mp=106.8-107.5°C.).

Step 3

The carbamate (2) from Step 2 (7.6 g, 27.5 mmol) was dissolved in 70 mLTHF and added over a period of 30 min. to a stirred slurry of 3 g (75mmol) of LAH in 300 mL of diethyl ether. The mixture was stirred atreflux for 8 h and allowed to stand at ambient temperature for 16 h. Thereaction was quenched while stirring by sequential addition of 1—water;2—15% NaOH and 3—water until all solids appeared to be white. The solidswere removed by filtration and washed once with THF. The filtrates werecombined, concentrated under reduced pressure, and the remaining oil wasdistilled to yield 4.1 g (78%) of the N-methylbenzylamine (3). Bp 140°C./1 mm.

Step 4

A sample of 2-chloro-6,7-dimethoxyquinazolin-4-one (300 mg, 1.25 mmol)in 4-5 mL of 1,2-dihydroxypropane was allowed to react with (400 mg, 2.1mmol) of benzylamine (3) for 16 h at 110° C. The solvent was removed invacuo and the remaining solid was chromatographed (EM Science silica gel60; 2% MeOH in DCM) to yield 300 mg (60%) of the above titled-compoundExample A-1. Mp 238-40° C.; MS m/z 395 (M+H). The bis HCl salt wasobtained when the free base in hot EtOH was treated with an excess of10% HCl in EtOH, and was crystallized by addition of diethyl ether. Mp220-223° C. Anal. (C₂₂H₂₆N₄O₃.2HCl), Calcd.: C, 56.54; H, 6.04; N,11.99. Found: C, 56.20; H, 6.01; N, 11.95.

Example A-22-[Benzyl-(1-benzyl-piperidin-4-yl)-amino]-6,7-dimethoxy-1H-quinazolin-4-one;compound with trifluoro-acetic acid

Step 1

Benzylamine (1) was prepared following the procedure of Harper et al.,Journal of Medicinal Chemistry, Vol. 7(6) (1964), at pp. 729-32.

Step 2

The benzylamine (1) (14 mg) and 2-chloro-6,7-dimethoxyquinazolin-4-one(12 mg) were heated together in NMP at 80° C. for 3 d. Purification byRP-HPLC provided the title compound: m/z 485 (M+H)⁺.

Examples A-3 to A-16

Compounds having the above formula (Ih), wherein R¹⁰ and Y—Ar consideredtogether have the values reported in Table 1, were prepared followingthe same or similar method as described above for Example A-1, exceptthe appropriately-substituted amine was used in place ofN-methyl-(3-pyrrolidin-1-yl-benzyl)-amine. TABLE 1 MS Ex. R¹⁰ —Y—ArCompound Name Mp ° C. (M+H)⁺ A-3 —CH₃

6,7-Dimethoxy-2-[methyl-(6- methyl-pyridin-2-ylmethyl)-amino]-1H-quinazolin-4-one 341 A-4 —CH₃

2-{[2-(1H-Indol-3-yl)-ethyl]- methyl-amino}-6,7-dimethoxy-1H-quinazolin-4- one 379 A-5 —CH₃

6,7-Dimethoxy-2-{methyl-[3- (4-methyl-piperazin-1-yl)-benzyl]-amino}-1H- quinazolin-4-one 424 A-6 —H

6,7-Dimethoxy-5-methyl-2-[2- (4-methyl-piperazin-1-yl)-benzylamino]-1H-quinazolin- 4-one 424 A-7 —isoPr

2-(Benzyl-isopropyl-amino)- 6,7-dimethoxy-1H-quinazolin- 4-one 168-170.5354 A-8 —CH₃

N′-(3-{[(6,7-Dimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}- phenyl)-N,N-dimethyl- formamidine,hydrochloride salt 242-245 395.4 M⁺ A-9 —CH₃

2-{[3-(4,5-Dihydro-3H-pyrrol- 2-ylamino)-benzyl]-methyl-amino}-6,7-dimethoxy-1H- quinazolin-4-one 211-14 407.5 M⁺ A-10 —CH₃

N-(3-{[(6,7-Dimethoxy-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}- phenyl)-acetamidine, hydrogen bromide salt 263-66381.4 M⁺ A-11 —CH₃

2-{[3-(4,5-Dihydro-1H- imidazol-2-ylamino)-benzyl]- methyl-amino}-6,7-dimethoxy-1H-quinazolin-4- one 409 A-12 —CH₃

2-{[3-(4,4-Dimethyl-4,5- dihydro-imidazol-1-yl)-benzyl]-methyl-amino}-6,7- dimethoxy-1H-quinazolin-4- one 240-244 422A-13 —CH₃

N′-(3-{2-[(6,7-Dimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-ethyl}- phenyl)-N,N-dimethyl- acetamidine 135-138.1423.5 M⁺ A-14 —CH₃

6,7-Dimethoxy-2-(methyl-{2- [3-(pyrimidin-2-ylamino)-phenyl]-ethyl}-amino)-1H- quinazolin-4-one 433 A-15 —CH₃

2-[(2-{3-[(1H-Imidazol-2- ylmethyl)-amino]-phenyl}-ethyl)-methyl-amino]-6,7- dimethoxy-1H-quinazolin-4- one 435 A-16 —CH₃

2-{[2-(3,4-Dimethoxy- phenyl)-ethyl]methyl-amino}-6,7-dimethoxy-1H-quinazolin- 4-one 400

Additional compounds prepared according to the procedure of Example A-1using various aralkylamines with 2-chloro-6,7-dimethoxyquinazolin-4-oneare shown in Table 11.

Example B-12-[(3-Amino-benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one

Step 1: 2-Chloro-6,7-dimethoxy-5-methyl-quinazolin-4-one

A solution of 3 g (11 mmol) of the dichloroquinazoline (1A) in 50 mL THFwas stirred with 30 mL of 40% aqueous KOH and 3 mL of 40% aqueoustetrabutylammonium hydroxide for 3 days. The layers were allowed toseparate and the upper layer was concentrated to give a white solid.This was treated with dilute acetic acid and the solid was collected andwashed with water, then dried at 65° C. in vacuo to afford 2.4 g (86%)of the 2-chloroquinazolin-4-one (1). Mp 251-251.7° C.; MS (ES+) m/z 255(M+H)⁺. Anal. (C₁₁H₁₁ClN₂O₃) Calcd.: C, 51.88; H, 4.35; N, 11.00. Found:C, 51.94; H, 4.34; N, 10.95.

Step 2

A mixture consisting of the 2-chloroquinazolin-4-one (1) from Step 1(2.95 g, 11.6 mmol), the above benzylamine (2) (1.65 g, 12.2 mmol), andN,N-diisopropylethylamine (1.5 g, 11.6 mmol) in 45 mL of EtOH was placedin a heavy-walled glass reaction vessel. A magnetic stirring bar wasadded and the reaction vessel was closed. The reaction mixture formed aslurry, and it was stirred while the reaction vessel was kept partiallyimmersed in an 120° C. bath for 2 h. The mixture was allowed to remainat ambient temperature without stirring for 16 h. The solid product wascollected, washed twice with EtOH, and dried at 65° C. in vacuofurnishing 3.7 g (90%) of Example B-1 as an off-white solid. Mp268-269.5° C.; Anal. (C₁₉H₂₂N₄O₃) Calcd.: C, 64.39; H, 6.26; N, 15.81.Found: C, 64.05; H, 6.25; N, 15.49.

Example B-23-{[(6,7-Dimethoxy-5-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzonitrile

Diisopropylethylamine (0.82 mL, 4.71 mmol) was added to a mixture of2-chloro-6,7-dimethoxy-5-methylquinazolin-4-one (1.0 g, 3.92 mmol) andN-methyl-(3-cyano-benzyl)-amine (0.68 g, 4.71 mmol) in EtOH (50 mL). Themixture was heated at 120° C. for 1.5 h in a sealed tube. After cooling,the resulting white solid was filtered and washed with MeOH to providethe arylnitrile of Example B-2. Mp 279.9-281.5° C.; ¹H NMR (DMSO-d6) δ2.6 (s, 3H), 3.05 (s, 3H), 3.62 (s, 3H), 3.84 (s, 3H), 4.86 (s, 2H),6.62 (s, 1H), 7.5-7.7.78 (m, 4H); ¹³C NMR (DMSO-d6) δ 13.89, 35.58,51.52, 55.93, 60.22, 104.79, 111.78, 119.15, 130.12, 131.19, 131.28,131.96, 132.51, 140.04, 142.96, 150.51, 157.71. MW=365.

Examples B-3 to B-10

Compounds having the above formula (II), wherein R⁵, R⁷ and R¹⁰ have thevalues reported in Table 2 were prepared following the same or similarmethod as described for Examples B-1 and B-2. TABLE 2 MS Ex. R⁵ R⁷ R¹⁰Compound Name Mp ° C. (M+H)⁺ B-3 —CH₃ —H

2-[Benzyl-(2- dimethylamino- ethyl)-amino]-6,7- dimethoxy-5- methyl-1H-quinazolin-4-one 397 B-4 —CH₃ 3-Br —CH₃ 2-[(3-Bromo- 419 benzyl)-methyl-amino]-6,7- dimethoxy-5- methyl-1H- quinazolin-4-one B-5 —O—CH₃ 3-Br—CH₃ 2-[(3-Bromo- 435 benzyl)-methyl- amino]-5,6,7- trimethoxy-1H-quinazolin-4-one B-6 —CH₃ 2-F —CH₂CH₂OH 2-[(2-Fluoro- 388 benzyl)-(2-hydroxy-ethyl)- amino]-6,7- dimethoxy-5- methyl-1H quinazolin-4-one B-7—O—CH₃ 3-cyano —CH₃ 3-{[Methyl-(5,6,7- 381 trimethoxy-4-oxo-1,4-dihydro- quinazolin-2-yl)- amino]-methyl}- benzonitrile B-8 —CH₃3-NH(CH₃) —CH₃ 6,7-Dimethoxy-5- 368.4 M⁺ methyl-2-8 methyl-(3-methylamino- benzyl)-amino]- 1H-quinazolin-4- one B-9 —O—CH₃ 3-NH₂—CH₃ 2-[(3-Amino- 225-226.5 370.4 M⁺ benzyl)-methyl- amino]-5,6,7-trimethoxy-1H- quinazolin-4-one B-10 —O—CH₃ 2-NH₂ —CH₃ 2-[(2-Amino-370.4 M⁺ benzyl)-methyl- amino]-5,6,7- trimethoxy-1H- quinazolin-4-one;

Additional compounds prepared according to the procedure of Examples B-2and B-3 are shown in Table 11.

Example C-1 6,7-Dimethoxy-5-methyl-2-[meth1-(3-methylaminomethyl-benzyl)-amino]-1H-quinazolin-4-one

Step 1

3-(Bromomethyl)benzoate (5.0 g, 21.83 mmol) and 40% methylamine in water(40.0 mL, 515.2 mmol) in EtOH (17 mL) were heated at 80° C. for 6 h. Thesolvent was concentrated to dryness. Purification by flashchromatography (CH₂Cl₂:MeOH: NH₄OH/300:10:1) gave 2.71 g (70%) ofcompound (1) above as a clear oil.

Step 2

1.0 M LiAlH₄ in THF (30.32 mL, 30.42 mmol) was added to compound (1)(2.71 g, 15.01 mmol) in THF (20 mL), and the mixture was heated atreflux for 16 h. After cooling to rt, Na₂SO₄.8H₂O (ca. 5 g) was added,and the heterogeneous solution was stirred at rt for 0.5 h. The whitesolid was filtered off and the filtrate was concentrated to dryness.Purification by flash chromatography (CH₂Cl₂: MeOH: NH₄OH/60:10:1) gave1.17 g (48%) of the above compound (2) as a clear oil.

Step 3

2-Chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one (0.805 g, 3.16 mmol)and compound (2) (0.675 g, 4.109 mmol) in EtOH (10 mL) were heated in asealed tube at 120° C. for 3 h. The solvent was evaporated to drynessunder reduced pressure. Purification by flash chromatography (CH₂Cl:MeOH: NH₄OH/320:10:1) followed by recrystallization (CH₂Cl₂/ether) gave0.468 g (39%) of the above Example C-1 as a white solid. mp 179.0-181.3°C.; ¹H NMR (DMSO-d₆, 2.49) δ 1.74 (s, 3H), 2.54 (t, 2H), 2.80 (s, 3H),2.97 (s, 6H), 3.62 (s, 3H), 3.75 (t, 2H), 3.86 (2, 3H), 4.72 (s, 2H),6.40 (d, 1H), 6.67 (s, 1H), 6.75 (d, 2H), 7.05 (t, 1H), 10.99 (s, 1H);IR (KBr) v_(max) 1589 cm⁻¹; MS (ES+) m/z 383(M+H); Anal. (C₂₁H₂₆N₄O₃) C:calcd, 65.95; found, 65.75; H: calcd, 6.85; found, 6.76; N: calcd,14.65; found, 14.66.

Examples C-2 to C-24

Compounds having the above formula (Ij), wherein R⁵, R⁷ and R¹⁰ have thevalues reported in Table 3, were prepared following the same or similarmethod as described for Example C-1. TABLE 3 MS Ex. R⁵ —R⁷ R¹⁰ CompoundName Mp ° C. (M+H) C-2 —CH₃ —CH₂—NH₂ —CH₃ 2-[(3-Aminomethyl- 369benzyl)-methyl-amino]- 6,7-dimethoxy-5-methyl- 1H-quinazolin-4-one C-3—O—CH₃ —CH₂CN —CH₃ (3-{[Methyl-(5,6,7- 395 trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-phenyl)- acetonitrile C-4—O—CH₃ —CH₂OH —CH₃ 2-[(3-Hydroxymethyl- 386 benzyl)-methyl-amino]-5,6,7-trimethoxy-1H- quinazolin-4-one C-5 —OH —CH₂OH —CH₃5-Hydroxy-2-[(3- 372 hydroxymethyl-benzyl) methyl-amino]-6,7-dimethoxy-1H- quinazolin-4-one C-6 —O—CH₃

—CH₃ 5,6,7-Trimethoxy-2- [methyl-(3-morpholin-4-ylmethyl-benzyl)-amino]- 1H-quinazolin-4-one 455 C-7 —O—CH₃ —CH₂NH(CH₃₎—CH₃ 5,6,7-Trimethoxy-2- 124.9-127.6 398.5 M⁺ [methyl-(3-methylaminomethyl- benzyl)-amino]-1H- quinazolin-4-one C-8 —CH₃

—CH₂CH₃ 2-[Ethyl-(3- methylaminomethyl- benzyl)-amino]-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 396.5 M⁺ C-9 —CH₃

—CH₃ 2-[(3-Ethylaminomethyl- benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl- 1H-quinazolin-4-one 396.5 M⁺ C-10 —O—CH₃

—CH₃ 2-({3-[(Ethyl-methyl- amino)-methyl]-benzyl}- methyl-amino)-5,6,7-trimethoxy-1H- quinazolin-4-one 426.5 M⁺ C-11 —CH₃

—CH₃ 6,7-Dimethoxy-5-methyl- 2-(methyl-{3-[(2,2,2-trifluoro-ethylamino)- methyl]-benzyl}-amino)- 1H-quinazolin-4-one 450.5M⁺ C-12 —O—CH₃

—CH₃ 2-[(3-{[(2-Hydroxy- ethyl)-methyl-amino]- methyl}-benzyl)-methyl-amino]-5,6,7-trimethoxy- 1H-quinazolin-4-one hydrochloride salt169.0-171.9 456.5 M⁺ C-13 —CH₃

—CH₃ 6,7-dimethoxy-5-methyl- 2-[(3-{[(2-methoxy- ethyl)-methyl-amino]-methyl}-benzyl)-methyl- amino]-1H-quinazolin-4- one 426.5 M⁺ C-14 —O—CH₃

—CH₃ 5,6,7-Trimethoxy-2-[(3- {[(2-methoxy-ethyl)- methyl-amino]-methyl}-benzyl)-methyl-amino]- 1H-quinazolin-4-one hydrogen chloride salt162.9-164.5 470.6 M⁺ C-15 —O—CH₃

—CH₃ 2-[(3-{[Ethyl-(2- methoxy-ethyl)-amino]- methyl}-benzyl)-methyl-amino]-5,6,7-trimethoxy- 1H-quinazolin-4-one hydrogen chloride salt470.6 M⁺ C-16 —CH₃

—CH₃ N-(3-{[(6,7-Dimethoxy- 5-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)- methyl-amino]-methyl}- benzyl)-2-methoxy-N-methyl-acetamide 454.5 M⁺ C-17 —O—CH₃

—CH₃ 2-Methoxy-N-methyl-N- (3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-benzyl)- acetamide 115-117470.5 M⁺ C-18 —CH₃

—₃ 2-[(3-{[Ethyl-(2- methoxy-ethyl)-amino]- methyl}-benzyl)-methyl-amino]-6,7-dimethoxy-5- methyl-1H-quinazolin-4- one 454.6 M⁺ C-19 —CH₃

—CH₃ 6,7-Dimethoxy-5-methyl- 2-[methyl-(3-pyrrolidin-1-ylmethyl-benzyl)- amino]-1H-quinazolin-4- one 422.5 M⁺ C-20 —OH

—CH₃ 5-Hydroxy-6,7- dimethoxy-2-{methyl-[3- (1-methyl-4,5-dihydro-1H-imidazol-2-ylmethyl)- benzyl]-amino}-1H- quinazolin-4-one 438 C-21—O—CH₃

—CH₃ 5,6,7-Trimethoxy-2- {methyl-[3-(1-methyl- 4,5-dihydro-1H-imidazol-2-ylmethyl)-benzyl]- amino}-1H-quinazolin-4- one 452 C-22 —OH

—CH₃ 5-Hydroxy-2-{[3-(1- isopropyl-4,5-dihydro- 1H-imidazol-2-ylmethyl)-benzyl]-methyl-amino}- 6,7-dimethoxy-1H- quinazolin-4-one 466 C-23—O—CH₃

—CH₃ 2-{[3-(1-Isopropyl-4,5- dihydro-1H-imidazol-2- ylmethyl)-benzyl]-methyl-amino}-5,6,7- trimethoxy-1H- quinazolin-4-one 480 C-24 —O—CH₃

—CH₃ 5,6,7-Trimethoxy-2- {methyl-[3-(1-methyl- piperidin-4-ylmethyl)-benzyl]-amino}-1H- quinazolin-4-one 466.6 M⁺

Additional compounds prepared according to the procedure of Example C-1are shown in Table 11.

Examples D-1 to D-8, E-1 to E-15

Compounds having the above formula (Ik), wherein R⁵, R⁷ and R¹⁰ have thevalues reported in Tables 4 and 5, were prepared following the same orsimilar method as described for the above Examples. TABLE 4 Ex. R⁵ R⁷R¹⁰ Compound Name Mp ° C. MS (M⁺ D-1 —CH₃ —SO₂CH₃ —CH₃ 2-[(3-269.5-271.5 417.5 Methanesulfonyl benzyl)-methyl- amino]-6,7-dimethoxy-5-methyl- 1H-quinazolin-4-one D-2 —O—CH₃ —SO₂CH₃ —CH₃ 2-[(3-231.5-232.9 433.5 Methanesulfonyl- benzyl)-methyl- amino]-5,6,7-trimethoxy-1H- quinazolin-4-one D-3 —O—CH₃

—CH₃ N,N-(5,6,7- {[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}- benzenesulfonamide 462.5 D-4—CH₃

—CH₃ 3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4- dihydro-quinazolin-2-yl)-methyl-amino]- methyl }-N-(2- methoxy-ethyl)- benzenesulfonamide476.6 D-5 —O—CH₃

—CH₃ N-(2-Methoxy-ethyl)- 3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}- benzenesulfonamide 492.6 D-6—CH₃

—CH₃ 3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4- dihydro-quinazolin-2-yl)-methyl-amino]- methyl}-N-(3- methoxy-propyl)- benzenesulfonamide490.6 D-7 —CH₃ —CO₂H —CH₃ 3-{[(6,7-Dimethoxy-5- 383.4 methyl-4-oxo-1,4-dihydro-quinazolin-2- yl)-methyl-amino]- methyl}-benzoic acid D-8 —O—CH₃—CO₂H —CH₃ 3-{[Methyl-(5,6,7- 400 (M+H)⁺ trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}- benzoic acid

TABLE 5 Ex. R⁵ R⁷ R¹⁰ Compound Name Mp ° C. MS (M+H) E-1 —CH₃ 13C(═O)NHCH₃ —CH₃ 3-{[(6,7-Dimethoxy-5-methyl- 243.3-245.1 396.4 M⁺4-oxo-1,4-dihydro-quinazolin- 2-yl)-methyl-amino]-methyl}-N-methyl-benzamide E-2 —O—CH₃ —C(═O)NHCH₃ —CH₃N-Methyl-3-{[methyl-(5,6,7- 217.9-219.1 412.4 M⁺trimethoxy-4-oxo-1,4-dihydro- quinazolin-2-yl)-amino]- methyl}-benzamideE-3 —O—CH₃

—CH₃ N-(2-Dimethylamino-ethyl)-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}-benzamide 470 E-4—O—CH₃

—CH₃ N-(2-Dimethylamino-ethyl)-N- methyl-3-{[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro- quinazolin-2-yl)-amino]- methyl}-benzamide484 E-5 —O—CH₃

—CH₃ N-(3-Dimethylamino-propyl)- N-methyl-3-{[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro- quinazolin-2-yl)-amino]- methyl}-benzamide498 E-6 —O—CH₃

—CH₃ N-(2-Hydroxy-ethyl)-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}-benzamide 443 E-7—O—CH₃

—CH₃ N-(2-Hydroxy-propyl)-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}-benzamide 457 E-8—O—CH₃

—CH₃ N-(2-Hydroxy-ethyl)-N- methyl-3-{[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro- quinazolin-2-yl)-amino]- methyl}-benzamide457 E-9 —O—CH₃

—CH₃ N-(2-Methoxy-ethyl)-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}-benzamide 457 E-10—O—CH₃

—CH₃ N-(3-Methoxy-propyl)-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}-benzamide 471 E-11—O—CH₃

—CH₃ N-Cyanomethyl-3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-benzamide 438 E-12 —O—CH₃

—CH₃ 3-{[Methyl-(5,6,7-trimethoxy- 4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-N- (tetrahydro-furan-2-ylmethyl)- benzamide 483E-13 —O—CH₃

—CH₃ N-Furan-2-ylmethyl-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2- yl)-amino]-methyl}-benzamide 479 E-14—O—CH₃

—CH₃ 3-{[Methyl-(5,6,7-trimethoxy- 4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-N-(2- morpholin-4-yl-ethyl)- benzamide 512 E-15—O—CH₃

—CH₃ 2-{[3-(4-Hydroxymethyl- piperidine-1-carbonyl)-benzyl]-methyl-amino}-5,6,7- trimethoxy-1H-quinazolin-4- one 497

Example F-12-{[3-(2-Hydroxy-ethoxy)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one

Step 1: 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde

TBDMSCI silylation reagent in DMF (60 mL) was added to3-(2-hydroxy-ethoxy)-benzaldehyde (4.985 g, 30.00 mmol). The mixture wasstirred at room temperature for 72 h. The mixture was diluted with waterand extracted with diethyl ether. The ethereal extracts were dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by SiO₂eluted with 95:5 CH₂Cl₂/MeOH to give 2.38 g (28%) of a clear oil.

Step 2:{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzylidene}-methyl-amine

3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde (2.375 g,8.47 mmol) was dissolved in 10 mL EtOH. MeNH₂ (1.2 mL, 40% in H₂O) wasadded and the mixture was heated to 40° C. for 30 min. The mixture wasthen concentrated in vacuo. The aqueous residue was diluted withisopropanol and then concentrated in vacuo. This was repeated twice moregiving 2.184 g (87.89%) of a dry white powder.

Step 3:{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzyl}-methyl-amine

{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzylidene}-methyl-amine(1.174 g, 4.00 mmol) was dissolved in EtOH and cooled to 0° C. NaH₄ (189mg, 5.00 mmol) was added and the mixture was allowed to stir for 4 h.The reaction was carefully quenched with water. The EtOH was removed invacuo. The aqueous residue was extracted with CH₂Cl₂. The organicextracts were dried over Na₂SO₄ and concentrated in vacuo to give 1.185g (quant) of a white powder.

Step 4:2-({3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzyl}-methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4-one

{3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzyl}-methyl-amine fromStep 3 (294 mg, 1.00 mmol) and2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (prepared as describedpreviously) (270 mg, 1.00 mmol) were dissolved in dry DMSO. Et₃N (0.14mL, 1.00 mmol) was added and the mixture was heated to 120° C.overnight. Upon cooling, the mixture was poured into water and extractedwith diethyl ether. The ethereal extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by SiO₂ eluted with 99:1CH₂Cl₂/MeOH to give 435 mg (82.12%) of a white crystalline solid.

Step 5:2-{[3-(2-Hydroxy-ethoxy)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one

Compound from step 4 (431 mg, 0.82 mmol) was dissolved in dry THF (15mL). Bu₄NF (0.82 mL, 1.0 M in THF) was added and the mixture was stirredovernight. The mixture was concentrated in vacuo. The residue wasdissolved in hot MeOH and allowed to stand for crystallization. A smallfraction of diethyl ether was added to induce crystallization. The solidwas filtered and dried to give 56 mg (16.57%) of a white crystallinesolid. mp 146.0-147.5° C.; ¹H NMR (D₂O-d₂) δ 3.19 (s, 3H), 3.86 (s, 3H),3.88 (s, 3H), 3.89 (t, 2H, J=4.4), 3.92 (s, 3H), 4.04 (t, 2H, J=4.4),4.85 (s, 2H), 6.63 (s, 1H), 6.83 (m, 3H), 7.23 (t, 1H, J=7.8);

¹³C NMR (DMSO-d₆, 39.50) δ 35.57, 52.90, 56.37, 61.81, 61.83, 62.16,69.55, 102.77, 104.74, 113.65, 114.35, 120.55, 130.24, 138.86, 139.30,150.96, 151.03, 153.47, 159.45, 159.56, 162.81; MS (ES+) m/z 416 (M+H);Anal. (C₂₁H₂₅N₃O₆) C: calcd, 60.71; found, 60.39; H: calcd, 6.07; found,5.97; N: calcd, 10.11; found, 10.01.

Example F-22-[(3-Methanesulfinylmethoxy-benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one

Step 1: 3-Methylsulfanylmethoxy-benzaldehyde

3-Hydroxybenzaldehyde (6.106 g, 50.00 mmol) was dissolved in acetone atroom temperature. K₂CO₃ (13.821 g, 100.00 mmol), NaI (7.569 g, 50.00mmol) and chloromethyl methyl sulfide (4.19 mL, 50.00 mmol) were added,and the mixture was allowed to stir for 80 h. The mixture was filtered,the filtrate concentrated to an oil, and the residue purified by SiO₂eluted with 99:1 CH₂Cl₂/MeOH to give 3.309 g (36.31%) of a yellow oil.

Step 2: Methyl-(3-methylsulfanylmethoxy-benzylidene)-amine

3-Methylsulfanylmethoxy-benzaldehyde from step 1 (3.309 g, 18.16 mmol)was dissolved in EtOH (9 mL). MeNH₂ (2.55 mL, 40% in H₂O) was added andthe mixture was heated to 40° C. for 30 min. Upon cooling, the mixturewas concentrated in vacuo. The aqueous residue was diluted withisopropanol and then concentrated in vacuo. This was repeated twice moregiving 3.55 g (quant) of a pale yellow oil.

Step 3: Methyl-(3-methylsulfanylmethoxy-benzyl)-amine

Compound from step 2 (3.546 g, 18.16 mmol) was dissolved in EtOH (50 mL)and cooled to 0° C. NaBH₄ (859 mg, 22.70 mmol) was added and the mixturewas allowed to stir for 4 h. The reaction was carefully quenched withwater. The EtOH was removed in vacuo. The aqueous residue was extractedwith CH₂Cl₂. The organic extracts were dried over Na₂SO₄ andconcentrated in vacuo to give 2.044 g (57%) of a clear yellow oil.

Step 4: (3-Methanesulfinylmethoxy-benzyl)-methyl-amine

Compound from step 3 (592 mg, 3.00 mmol) was dissolved in glacial aceticacid (4 mL) and cooled to 0° C. H₂O₂ (0.34 mL, 3.00 mmol) was addeddrop-wise. The mixture was allowed to stir for 6 h. The mixture was thendiluted with CH₂Cl₂ and neutralized with K₂CO₃. The solids were filteredoff. The filtrate was dried over Na₂SO₄ and concentrated in vacuo togive 640 mg (quant) of a yellow crystalline solid.

Step 5:2-[(3-Methanesulfinylmethoxy-benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one

Compound from step 4 (213 mg, 1.00 mmol) and2-chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one (254 mg, 1.00 mmol)were dissolved in dry DMSO. Et₃N (0.14 mL, 1.00 mmol) was added, and themixture was heated to 120° C. overnight. Upon cooling, the mixture waspoured into water and extracted with diethyl ether. The etherealextracts were dried over Na₂SO₄ and concentrated in vacuo. The residuewas recrystallized from MeOH to give 54 mg (12.53%) of the above ExampleF-2 as a white crystalline powder. mp 191.0-193.5° C.; ¹H NMR (DMSO-d₆,2.49) δ 2.59 (s, 3H), 2.60 (s, 3H), 3.03 (s, 3H), 3.62 (s, 3H), 3.84 (s,3H), 4.79 (s, 2H), 5.02 (d, 1H, J=10.6), 5.22 (d, 1H, J=10.6), 6.64 (s,1H), 6.90 (d, 1H, J=7.6), 7.01 (m, 2H), 7.30 (t, 1H, J=7.9); 13c NMR(DMSO-d₆, 39.50) δ 13.90, 34.66, 35.59, 51.90, 55.93, 60.23, 84.92,104.81, 108.46, 114.18, 115.02, 121.22, 130.13, 131.94, 140.10, 142.90,150.63, 150.97, 157.71, 157.97, 163.67; MS (ES+) m/z 432 (M+H); Anal.(C₂₁H₂₅N₃O₅S)C: calcd, 58.45; found, 58.32; H: calcd, 5.84; found, 5.74;N: calcd, 9.74; found, 9.77.

Example F-36,7-Dimethoxy-5-methyl-2-{methyl-[3-(pyrimidin-2-yloxy)-benzyl]-amino}-1H-quinazolin-4-one

Step 1

A mixture of 3-hydroxybenzaldehyde (2.00 g, 16.38 mmol),2-chloropyrimidine (1.88 g, 16.38 mmol) and ^(i)Pr₂NEt (5.71 mL, 32.75mmol), under N₂ atmosphere was heated at 105° C. for 24 h. The reactionmixture was allowed to cool to room temperature. The crude was subjectedto column chromatography (silica gel, 20% EtOAc in hexanes) to furnish1.62 g of the desired aryl ether (1) as an off-white solid.

Step 2

To a solution of the aryl ether (1) from Step 1 (1.00 g, 5.00 mmol) andMeNH₂ (3.00 mL, 2.0 M in THF, 5.99 mmol) in MeOH (75 mL) at roomtemperature was added NaCNBH₃ (377 mg, 5.99 mmol). The reaction wasstirred for 7 h before it was concentrated under reduced pressure. Theresidue was taken-up in a mixture of 1 N aq. HCl (20 mL) and CH₂Cl₂ (5mL). The aq. layer was separated, adjusted to pH 10, and extracted withCH₂Cl₂. The CH₂Cl₂ extract was washed with brine, dried over MgSO₄, andconcentrated. The residue was purified by column chromatography (silicagel, 10% MeOH in CH₂Cl₂) to furnish 363 mg of the benzylamine (2) as afaintly-colored oil.

Step 3

A mixture of the benzylamine (2) from Step 2 (152 mg, 0.71 mmol),2-chloro-6,7-dimethoxy-5-methyl-quinazolin-4-one (150 mg, 0.59 mmol) and^(i)Pr₂NEt (205 □L, 1.18 mmol) in anhydrous EtOH (5 mL) in a sealed tubewas heated at 65° C. for 16 h before it was allowed to cool to roomtemperature slowly. The precipitate was collected by suction filtration,washed with EtOH, and dried in the oven at 60° C. to provide 57 mg ofExample F-3 as an off-white solid. Mp 224.0-227.8° C.; TLC R_(f) 0.52(5% MeOH in CH₂Cl₂); ¹H NMR (DMSO-d₆, 2.49) δ 2.60 (s, 3H), 3.05 (s,3H), 3.62 (s, 3H), 3.83 (s, 3H), 4.85 (s, 2H), 6.62 (br s, 1H),7.08-7.13 (m, 3H), 7.24 (t, 1H, J=4.8 Hz), 7.40 (t, 1H, J=7.7 Hz), 8.60(d, 2H, J=4.8 Hz), 10.84 (br s, 1H); MS (ES+) m/z 434 (M+H); Anal.(C₂₃H₂₃N₅O₄.2HCl.0.5H₂O)C: calcd, 53.60; found, 53.55; H: calcd, 13.58;found, 13.52; N: calcd, 5.08; found, 4.48.

Examples F-4 to F-16

Compounds having the above formula (II), wherein R⁵, R⁷ and R¹⁰ have thevalues reported in Table 6 were prepared following the same or similarmethod as described for Examples F-1 through F-3. TABLE 6 Ex. R⁵ R⁷ R¹⁰Compound Name Mp ° C. MSM⁺ F-4 —CH₃ —OH —CH₃2-[(3-Hydroxy-benzyl)-methyl- 355.4 amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one F-5 —O—CH₃ —OH —CH₃ 2-[(3-Hydroxy-benzyl)-methyl-371.4 amino]-5,6,7-trimethoxy-1H quinazolin-4-one F-6 —O—CH₃

—CH₃ 2-[(3-Methanesulfonylmethoxy- benzyl)-methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 183.9-185.4 463.5 F-7 —CH₃

—CH₃ (3-{[(6,7-Dimethoxy-5-methyl- 4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}- phenoxy)-acetic acid 413.4 F-8 —O—CH₃

—CH₃ (3-{[Methyl-(5,6,7-trimethoxy- 4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-phenoxy)- acetic acid 429.4 F-9 —CH₃

—CH₃ 2-{[3-(2-Hydroxy-ethoxy)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 180.5-183.1 399.4 F-10 —CH₃

—CH₃ 6,7-Dimethoxy-2-{[3-(2- methoxy-ethoxy)-benzyl]-methyl-amino}-5-methyl-1H- quinazolin-4-one 144.8-145.9 413.5 F-11—O—CH₃

—CH₃ 5,6,7-Trimethoxy-2-{[3-(2- methoxy-ethoxy)-benzyl]-methyl-amino}-1H-quinazolin- 4-one 144.8-145.9 429.5 F-12 —CH₃

—CH₃ 6,7-Dimethoxy-2-{[3-(3- methoxy-propoxy)-benzyl]-methyl-amino}-5-methyl-1H- quinazolin-4-one 427.5 F-13 —O—CH₃

—CH₃ 5,6,7-Trimethoxy-2-{[3-(3- methoxy-propoxy)-benzyl]-methyl-amino}-1H-quinazolin- 4-one 443.5 F-14 —CH₃

—CH₃ 2-{[3-(2-Dimethylamino- ethoxy)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 426.5 F-15 —CH₃

—CH₃ 2-{[3-(2-Ethylamino-ethoxy)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 426.5 F-16 —O—CH₃

—CH₃ 5,6,7-Trimethoxy-2-{methyl-[3- (pyrimidin-2-yloxy)-benzyl]-amino}-1H-quinazolin-4-one 191-192.9 449.5

Additional compounds prepared according to the procedure of Examples F-1through F-3 are shown in Table 11.

Example G-1N′-(3-{[(6,7-Dimethoxy-5-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N-dimethyl-acetamidine

The aniline of Example B-1 (600 mg, 1.7 mmol), the dimethylacetal of DMF(330 mg, 2.23 mmol), and DMF (2 mL) was kept at 100° C. for 35 min andthen stored at ambient temperature for 16 h. The precipitated productwas collected and washed with diethyl ether affording 340 mg of product.This material was further purified by chromatography (EM Science silicagel 60; 3% MeOH in DCM containing 0.5% of ammonium hyrdroxide) to yield250 mg (35%) of the above compound as a white solid. Mp 174.4-174.8° C.;ms 424 (M+H). The HCl salt of the above compound was prepared mixing 600mg (1.4 mmol) of the free base with 8 mL hot EtOH, and then adding tothis solution 2.7 mL of a 1.4 M solution of HCl in EtOH (3.7 mmol). TheHCl salt was crystallized by addition of diethyl ether. The collectedproduct was dried at 80° C. in vacuo to furnish 620 mg. Mp 170.6-172.5°C.; Anal. (C₂₃H₂₉N₅O₃₀.2HCl.0.5H₂O) Calcd.: C, 54.65; H, 6.38; N, 13.86.Found: C, 54.40; H, 6.14; N, 13.81.

Examples G-2 to G-55

Compounds having the above formula (Im), wherein R⁵, R¹⁰ and Y—Ar takentogether have the values reported in Table 7, were prepared followingthe same or similar method as described for Example G-1. TABLE 7 Ex. NoR⁵ —Y—Ar Compound Name Mp ° C. MW G-2 IsoPr

N-(3-{[(5-Isopropyl-6,7- dimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)- methanesulfonamide215-17 460.55 G-3 —CH₃

6,7-Dimethoxy-5-methyl-2- [methyl-(3- [(dimethylamino)sulfonyl]amino]-benzyl)-amino]-1H- quinazolin-4-one 461.54 G-4 —CH₃

6,7-Dimethoxy-5-methyl-2- [methyl-(3-[(dimethyl amino)sulfonyl]methylamino]-benzyl)-amino]-1H- quinazolin-4-one 475.57 G-5 —O—CH₃

5,6,7-Trimethoxy-2-[methyl- (3-[(dimethylamino) sulfonyl]methylamino]-benzyl)-amino]-1H- quinazolin-4-one 477.54 G-6 —O—CH₃

5,6,7-Trimethoxy-2-[methyl- (3-[(dimethylamino) sulfonyl]methylamino]-benzyl)-amino]-1H- quinazolin-4-one 491.57 G-7 —CH₃

N-(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)- acetamide 396.45 G-8—O—CH₃

N-(3-{[Methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-phenyl)-acetamide 412.44 G-9 —O—CH₃

N-(4-Chloro-3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-phenyl)- acetamide 446.89 G-10—O—CH₃

1,1-Dimethyl-3-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-phenyl)-urea 441.49 G-11 —O—CH₃

(3-{[Methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-phenyl)-carbamic acid methyl ester428.44 G-12 —CH₃

(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro- quinazolin-2-yl-methyl-amino]-methyl}-phenyl)- methyl-carbamic acid methyl ester 426.47 G-13—CH₃

N-(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-N-methyl-2-oxo-propionamide 438.48 G-14 —CH₃

3-(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-1,1- dimethyl-urea425.49 G-15 —O—CH₃

1-Methoxy-3-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin- 2-yl)-amino]-methyl }- phenyl)-urea 443.46 G-16—O—CH₃

2-{[3-(2-Hydroxy- ethylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 60.5-61.4 414.46 G-17 —OH

5-Hydroxy-2-({3-[(3-hydroxy- propyl)-methyl-amino]-benzyl}-methyl-amino)-6,7- dimethoxy-1H-quinazolin-4- one 428.49 G-18—O—CH₃

2-{[3-(3-Hydroxy- propylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 47-48.5 428.49 G-19 —O—CH₃

5,6,7-Trimethoxy-2-{[3-(2- methoxy-ethylamino)-benzyl]-methyl-amino}-1H- quinazolin-4-one 178.9-179.9 428.49 G-20 —O—CH₃

5,6,7-Trimethoxy-2-({3-[(2- methoxy-ethyl)-methyl-amino]-benzyl}-methyl- amino)-1H-quinazolin-4-one 179.3-181.2 442.51G-21 —O—CH₃

2-({3-[(3 -Hydroxy-propyl)- methyl-amino]-benzyl}- methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4- one 156-157.2 442.51 G-22 —O—CH₃

5,6,7-Trimethoxy-2-{[3-(3- methoxy-propylamino)-benzyl]-methyl-amino}-1H- quinazolin-4-one, hydrochloride salt 442.51G-23 —O—CH₃

(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)- methyl-carbamic acidmethyl ester 455.5 G-24 —O—CH₃

2-({3-[Bis-(2-hydroxy-ethyl)- amino]-benzyl}-methyl-amino)-5,6,7-trimethoxy-1H- quinazolin-4-one 458.51 G-25 —CH₃

N-[2-(3-{1-[(6,7-Dimethoxy- 5-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-ethyl}-phenylamino)- ethyl]-acetamide453.54 G-26 —CH₃

N-(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)- acetamidine 155-58395.46 G-27 —O—CH₃

N-(3-{[Methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-phenyl)-acetamidine 411.46 G-28 —CH₃

N-(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-N,N′-dimethyl-acetamidine 423.51 G-29 —CH₃

N-(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-N′- methyl-acetamidine409.49 G-30 —CH₃

N′-(3-{[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl }-phenyl)-N,N-dimethyl-formamidine 185-86 409.49 G-31 —O—CH₃

N,N-Dimethyl-N′-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-phenyl)- acetamidine 199-201439.51 G-32 —O—CH₃

N,N-Dimethyl-N′-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-phenyl)- isobutyramidine 148-50467.57 G-33 —CH₂CH₃

N′-(3-{[(5-Ethyl-6,7- dimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-N,N-dimethyl-acetamidine 224.6-225.5 437.54 G-34 —isoPr

N′-(3-{[(5-Isopropyl-6,7- dimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-N,N-dimethyl-acetamidine 451.57 G-35 —OH

N′-(3-{[(5-Hydroxy-6,7- dimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-N,N-dimethyl-acetamidine 425.49 G-36 —O—CH₃

3-Methoxy-N,N-dimethyl-N′- (3-{[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin- 2-yl)-amino]-methyl}-phenyl)-propionamidine 145 483.57 G-37 —O—CH₃

N,N-Dimethyl-N′-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-phenyl)-cyclobutanecarboxamidine 479.57 G-38 —CH₃

2-{[3-(Imidazolidin-2- ylideneamino)-benzyl]- methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 141.3-144.7 422.49 G-39 —O—CH₃

5,6,7-Trimethoxy-2-{methyl- [3-(1-methyl-pyrrolidin-2-ylideneamino)-benzyl]- amino}-1H-quinazolin-4-one 130-133 451.52 G-40—O—CH₃

2-{[2-Chloro-5-(1,3-dimethyl- imidazolidin-2-ylideneamino)-benzyl]-methyl-amino}-5,6,7- trimethoxy-1H-quinazolin-4- one 500.98 G-41—CH₂—CH₃

2-{[3-(1,3-dimethyl- imidazolidin-2-ylideneamino)-benzyl]-methyl-amino}-6,7- diimethoxy-5-ethyl-1H- quinazolin-4-one,hexafluorophosphate 212.5-219.9 464.57 G-42 —CH₃

2-{[3-(4,5-Dihydro-3H-pyrrol- 2-ylamino)-benzyl[-methyl-amino{-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 175.4-177.2 421.50G-43 —O—CH₃

2-{[3-(4,5-Dihydro-3H-pyrrol- 2-ylamino)-benzyl]-methyl-amino{-5,6,7-trimethoxy-1H- quinazolin-4-one 207-209 437.50 G-44 —O—CH₃

5,6,7-Trimethoxy-2-{methyl- [3-(2-oxo-tetrahydro-furan-3-ylamino)-benzyl]-amino}-1H- quinazolin-4-one 454.48 G-45 —OH

2-({5-8 (4,5-Dihydro-3H- pyrrol-2-yl)-methyl-amino]-2-fluoro-benzyl}-methyl- amino)-5-hydroxy-6,7- dimethoxy-1H-quinazolin-4-one 455.49 G-46 —CH₃

6,7-Dimethoxy-5-methyl-2- {methyl-[3-(pyrimidin-2-ylamino)-benzyl]-amino}-1H- quinazolin-4-one 432.48 G-47 —O—CH₃

5,6,7-Trimethoxy-2-{methyl- [3 -(pyrimidin-2-ylamino)-benzyl]-amino}-1H- quinazolin-4-one 448.48 G-48 —O—CH₃

2-{[3-(2-Chloro-pyrimidin-4- ylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 482.93 G-49 —O—CH₃

2-{[3-(4-Chloro-pyrimidin-2- ylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 482.93 G-50 —CH₃

2-{[3-(4-Chloro-pyrimidin-2- ylamino)-benzyl]-methyl-amino}-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 466.93 G-51 —O—CH₃

2-{[3-(2-Chloro-5-methyl- pyrimidin-4-ylamino)-benzyl]-methyl-amino}-5,6,7- trimethoxy-1H-quinazolin-4- one 496.95 G-52 —O—CH₃

2-{[3-(2-Chloro-6-methyl- pyrimidin-4-ylamino)-benzyl]-methyl-amino}-5,6,7- trimethoxy-1H-quinazolin-4- one 496.95 G-53 —O—CH₃

2-{[3-(4-Chloro-6-methyl- pyrimidin-2-ylamino)-benzyl]-methyl-amino}-5,6,7- trimethoxy-1H-quinazolin-4- one 496.95 G-54 —O—CH₃

2-({3-[(1H-Imidazol-2- ylmethyl)-amino]-benzyl}- methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4- one 450.50 G-55 —F

N′-(3-{[(5-Fluoro-6,7- dimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl- amino]-methyl}-phenyl)-N,N-dimethyl-acetamidine 427.48

Additional compounds prepared according to the procedure of Example G-1are shown in Table 11.

Example H-15,6,7-Trimethoxy-2-{methyl-[3-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one

Step 1

To a solution of aniline (1) (1.39 g, 5.88 mmol) and ^(i)Pr₂NEt (1.13mL, 6.42 mmol) in THF (7 mL) at 0° C. was added dropwise a solution of4-chlorobutyryl chloride (659 □L, 5.88 mmol) in THF (3 mL). The reactionmixture was then allowed to warm to room temperature and stirred for 1 hbefore it was poured into a mixture of EtOAc and saturated aq. NH₄Cl.The organic layer was separated and concentrated under reduced pressureto provide the crude amide intermediate (2).

Step 2

To a solution of the amide intermediate (2) from Step 1 in MeCN (150 mL)at room temperature was added dropwise a solution of 50% aq. NaOH (0.94mL, 11.76 mmol). The reaction mixture was stirred for 1 h before it wasconcentrated under reduced pressure. The residue was partitioned betweenEtOAc and H₂O. The organic layer was washed with brine, dried overMgSO₄, and concentrated. The residue was purified (silica gel, EtOAc) tofurnish 1.80 g of lactam (3) as colorless oil.

Step 3

Trifluoroacetic acid (375 μL, 4.87 mmol) was added via syringe to astirred solution of (3) from Step 2 (189 mg, 0.62 mmol) at 0° C. After 3hours, the solution was concentrated under reduced pressure, then pumpedunder vacuum for 1 hour. The crude residue was dissolved in EtOH (2 mL),and added to a sealed tube containing2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (132 mg, 0.49 mmol),diisopropylethylamine (425 μL, 2.44 mmol), and EtOH (3 mL). Thesuspension was heated at 110° C. for 2 hours, then cooled to roomtemperature and stirred overnight. The reaction mixture was concentratedunder reduced pressure, and purified by chromatography to give 128 mg(60%) of the above Example H-1 as a cream colored solid. mp 165.5-166.5°C.; TLC Rf 0.5 (5% MeOH/DCM); IR (KBr) v_(max) 3429, 2933, 1657, 1592,1481, 1452, 1120, 1047, 933; ¹H NMR (DMSO-d₆, 2.49) 2.04 (m, 2H), 2.50(t, 2H, J=1.9),3.03 (s, 3H), 3.70 (s, 3H), 3.77 (s, 1H), 3.81 (t, 2H,J=6.9), 3.84 (s, 3H), 4.81 (s, 2H), 6.57 (s, 2H), 6.99 (d, 1H, J=7.7),7.32 (t, 1H, J=7.8), 7.49 (dd, 1H, J=2.1, 7.4), 7.65 (s, 1H), 10.83 (s,1H); MS (ES+) m/z 439 (M+H); Anal. (C₂₃H₂₆N₄O₅ w/0.25M CH₂Cl₂): calcd60.75; found: 60.65; H: calcd, 5.81; found: 5.79; N: calcd, 12.19;found, 11.98).

Example H-26,7-Dimethoxy-5-methyl-2-{methyl-[3-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-benzyl]-amino}-1H-quinazolin-4-one

Step 1

Diisopropylethylamine (0.82 mL, 4.71 mmol) was added to the mixture of2-chloro-6,7-dimethoxy-5-methyl-quinazolin-4-one (1.0 g, 3.92 mmol)andN-methyl-(3-cyano-benzyl)-amine (0.68 g, 4.71 mmol) in EtOH (50 mL). Itwas heated at 120° C. for 1.5 h in the sealed tube. After cooling down,the resulting white solid was filtered and washed with MeOH: mp279.9-281.5° C.; ¹H NMR (DMSO-d6) δ 2.6 (s, 3H), 3.05 (s, 3H), 3.62 (s,3H), 3.84. (s, 3H), 4.86 (s, 2H), 6.62 (s, 1H), 7.5-7.7.78 (m, 4H); ¹³CNMR (DMSO-d6) δ 13.89, 35.58, 51.52, 55.93, 60.22, 104.79, 111.78,119.15, 130.12, 131.19, 131.28, 131.96, 132.51, 140.04, 142.96, 150.51,157.71;

Step 2

α-Bromo-m-cyanotoluene (1.0 g, 5.1 mmol) in 2M MeNH₂/MeOH (25.5 mL, 51mmol) was refluxed for 1 h. After evaporating most of solvent, theresulting solid was filtered. The mother liquor was concentrated invacuo and it was purified by chromatography.

Step 3

A few drops of carbondisulfide was added to a solution of thearylnitrile of Example B-2, above (0.08 g, 0.219 mol) in 1 mL ofN-methylethylendiamine. The mixture was allowed to stir at 120° C. for 2h. The excess amine was evaporated under reduced pressure and purifiedby flash column chromatography to provide the above Example H-2. Mp145-148° C.; IR (KBr) v_(max) 2931, 1660, 1306 cm⁻¹; ¹H NMR (DMSO-d6) δ2.6 (s, 3H), 2.7 (s, 3H), 3.05.(s, 3H), 3.45 (t, 2H), 3.62 (s, 3H), 3.68(t, 2H), 3.84 (s, 3H), 4.86 (s, 2H), 6.65 (s, 1H), 7.3-7.45 (m, 4H); ¹³CNMR (DMSO-d6) δ 13.89, 35.60, 36.48, 39.05, 39.33, 39.60, 39.88, 51.82,52.54, 53.90, 55.93, 60.23, 127.01, 127.10, 128.97, 129.04, 131.40,131.98, 138.36, 142.94, 167.08; MS (ES+) m/z 422 (M+H); Anal.(C₂₃H₂₇N₅O₃.0.30M CH₂Cl₂) C; calcd, 62.61; found, 62.71; H; calcd, 6.22;found, 6.28; N; calcd, 15.67; found, 15.83.

Example H-36,7-Dimethoxy-5-methyl-2-{methyl-[3-(1-methyl-piperidin-4-yl)-benzyl]-amino}-1H-quinazolin-4-one

Step 1: 4-(3-Methylcarbamoylphenyl)piperidine-1-methylcarboxamide

To a solution of 4-(3-carboxyphenyl)piperidine-1-carboxylic acidtert-butyl ester (1.0 g, 3.27 mmol) in 4 mL of DMF, was added CDI (0.63g, 3.92 mmol) and the reaction mixture warmed to 60° C. for two hours.After that time, the mixture was cooled to 0-5° C. and, a 2 M solutionof methylamine in THF (4.91 mL, 9.82 mmol) was added via syringe and themixture allowed to warm to room temperature overnight. The mixture waspoured into a saturated solution of ammonium chloride, and the productwas extracted with ethyl ether (3×50 mL). Organics were washed withwater (3×30 mL) and brine (1×15 mL), then dried with magnesium sulfateand concentrated. The dense liquid, crude product, was used into thenext step without further treatment. Yield 1.05 g (100%). ¹H NMR (CDCl₃,7.26) δ 1.48 (s, 9H), 1.63 (m, 2H), 1.75 (m, 2H), 2.69 (m, 1H), 2.80 (m,2H), 3.01 (d, 3H), 4.23 (br s, 2H), 6.15 (br s, D₂O, 1H), 7.32 (dt, 1H,J=6.87, 1.71), 7.34 (t, 1H, J=6.72), 7.55 (dt, 1H, J=6.87, 1.71), 7.64(t, 1H, J=1.71); MS (ES+) m/z 319 (M+H), 341.2 (M+Na).

Step 2: Methyl-[3-(1-methylpiperidin-4-yl)benzyl]amine

To a solution of4-(3-methylcarbamoylphenyl)piperidine-1-methylcarboxamide (1.05 g, 3.29mmol) in 50 mL of THF, was added portion-wise LiAlH₄ (0.625 g, 16.48mmol). The reaction mixture was stirred at room temperature for 18 hoursand then warmed to 50° C. for 24 hours. Then, the mixture was cooled toroom temperature and Na₂SO₄.10H₂O (10 g) was added portion-wise (veryslowly), and the mixture stirred for two hours. Solids were removed byfiltration (celite pad), rinsed with 10% MeOH/CH₂Cl₂ (100 mL), and thefiltrate concentrated. The residue was purified by flash chromatography,eluting with CH₂Cl₂:MeOH:NH₄OH (60:10:1). Yield 0.59 g (81.9%). ¹H NMR(CDCl₃, 7.26) δ 1.64 (br s, D₂O, 1H), 1.82 (m, 4H), 2.04 (m, 2H), 2.32(s, 3H), 2.45 (s, 3H), 2.47 (m, 1H), 2.97 (m, 2H), 3.72 (s, 2H),7.13-7.18 (m, 3H), 7.26 (t, 1H, J=7.08); MS (ES+) m/z 219.2 (M+H).

Step 3:6,7-Dimethoxy-5-methyl-2-{methyl-[3-(1-methylpiperidin-4-yl)benzyl]amino}-1H-quinazolin-4-one

In a heavy-walled pressure tube, a mixture ofmethyl-[3-(1-methylpiperidin-4-yl)benzyl]amine (0.14 g, 0.64 mmol) and2-chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one (0.155 g, 0.60 mmol)in 4 mL of EtOH, was heated to 120° C. for 5 hours. After solventremoval, the residue was purified by flash chromatography eluting withCH₂Cl₂:MeOH:NH₄OH (94.5:5:0.5), and the above-titled Example H-3crystallized from CH₂Cl₂/cyclohexane. mp 155.7-158° C.; IR (KBr) v_(max)2933, 1651, 1590 cm; ¹H NMR (DMSO-d₆, 2.49) δ 1.59-1.71 (m, 4H), 1.93(m, 2H), 2.16 (s, 3H), 2.42 (m, 1H), 2.60 (s, 3H), 2.82 (m, 2H), 3.01(s, 3H), 3.62 (s, 3H), 3.84 (s, 3H), 4.78 (s, 2H), 6.63 (br s, 1H), 7.03(d, 1H, J=7.44), 7.11-7.13 (m, 2H), 7.25 (t 1H, J=7.74), 10.81 (br s,D₂O, 1H); ¹³C NMR (DMSO-d₆, 39.50) δ 13.44, 32.94, 35.12, 41.08, 46.09,51.64, 55.44, 55.65, 59.76, 124.61, 125.32, 125.65, 128.44, 137.54,146.43; MS (ES+) m/z 437 (M+H); Anal. (C₂₅H₃₂N₄O₃.0.25H₂O)C: calcd,68.08; found, 68.02; H: calcd, 7.43; found, 7.19; N: calcd, 12.70;found, 12.69.

Examples H-4 to H-47

Compounds having the above formula (In), wherein R³ and R⁷ have thevalues reported in Table 8, were prepared following the same or similarmethod as described for Examples H-1 to H-3, except using anappropriately substituted benzyl amine. TABLE 8 Ex. No —R⁵ —R⁷ CompoundName Mp ° C. MW H-4 —CH₃

6,7-Dimethoxy-5-methyl-2-[methyl-(3- pyrrolidin-1-yl-benzyl)-amino]-1H-quinazolin-4-one 408.50 H-5 —O—CH₃

5,6,7-Trimethoxy-2-[methyl-(3- pyrrolidin-1-yl-benzyl)-amino]-1H-quinazolin-4-one 424.50 H-6 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(2-methyl-4,5-dihydro-imidazol-1-yl)- benzyl]-amino}-1H-quinazolin-4-one177-180 421.50 H-7 —CH₃

2-{[3-(4,4-Dimethyl-4,5-dihydro- imidazol-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin- 4-one 435.53 H-8 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(2,4,4-trimethyl-4,5-dihydro-imidazol-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 449.55 H-9 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (4-methyl-imidazol-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 419.48 H-10 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (2-methyl-imidazol-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 419.48 H-11 —CH₃

6,7-Dimethoxy-5-methyl-2-[methyl-(3- pyrazol-1-yl-benzyl)-amino]-1H-quinazolin-4-one 405.46 H-12 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(3-methyl-pyrazol-1-yl)-benzyl]-amino}- 1H-quinazolin-4-one 220-223.5419.48 H-13 —CH₃

2-{[3-(3,5-Dimethyl-pyrazol-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 433.51H-14 —CH₃

6,7-Dimethoxy-5-methyl-2-[methyl-(3- pyrrolidin-2-yl-benzyl)-amino]-1H-quinazolin-4-one 408.50 H-15 —OCH₃

5,6,7-Trimethoxy-2-[methyl-(3- pyrrolidin-3-yl-benzyl)-amino]-1H-quinazolin-4-one 424.50 H-16 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-benzyl]-amino}-1H-quinazolin-4-one 421.50 H-17 —O—CH₃

5,6,7-Trimethoxy-2-{methyl-[3-(1- methyl-4,5-dihydro-1H-imidazol-2-yl)-benzyl]-amino}-1H-quinazolin-4-one 437.50 H-18 —CH₃

2-{[3-(1-Ethyl-4,5-dihydro-1H-imidazol- 2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 435.52 H-19 —O—CH₃

2-{[3-(1-Ethyl-4,5-dihydro-1H-imidazol-2-yl)-benzyl]-methyl-amino}-5,6,7- trimethoxy-1H-quinazolin-4-one 451.52H-20 —O—CH₃

2-{[3-(1-Isopropyl-4,5-dihydro-1H- imidazol-2-yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 465.55 H-21 —CH₃

2-{[4-(1-Isopropyl-4,5-dihydro-1H- imidazol-2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin- 4-one 449.55 H-22 —OH

5-Hydroxy-2-{[3-(1-isopropyl-4,5- dihydro-1H-imidazol-2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-1H- quinazolin-4-one; 451.52 H-23 —CH₃

2-{[4-(1-Isopropyl-4,5-dihydro-1H- imidazol-2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin- 4-one 449.55 H-24 —CH₃

2-({3-[1-(2-Hydroxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl]-benzyl}-methyl- amino)-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 451.52 H-25 —O—CH₃

2-({3-[1-(2-Hydroxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl]-benzyl}-methyl- amino)-5,6,7-trimethoxy-1H-quinazolin-4-one 467.52 H-26 —CH₃

6,7-Dimethoxy-2-({3-[1-(2-methoxy- ethyl)-4,5-dihydro-1H-imidazol-2-yl]-benzyl}-methyl-amino)-5-methyl-1H- quinazolin-4-one 465.55 H-27 —O—CH₃

5,6,7-Trimethoxy-2-({3-[1-(2-methoxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl]-benzyl}-methyl-amino)-1H-quinazolin-4- one 481.55 H-28 —CH₃

2-{[3-(1H-Imidazol-2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 405.46 H-29 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(1-methyl-1H-imidazol-2-yl)-benzyl]- amino}-1H-quinazolin-4-one 419.48H-30 —CH₃

2-({3-[1-(2-Hydroxy-ethyl)-1H-imidazol- 2-yl]-benzyl}-methyl-amino)-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 449.51 H-31 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}- 1H-quinazolin-4-one 422.48 H-32—CH₃

2-{[3-(1,1-Dioxo-11 6-isothiazolidin-2- yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 458.54 H-33 —OCH₃

2-{[3-(1,1-Dioxo-11 6-isothiazolidin-2- yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 474.54 H-34 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(2-oxo-oxazolidin-3-yl)-benzyl]-amino}- 1H-quinazolin-4-one 424.45 H-35—OCH₃

5,6,7-Trimethoxy-2-{methyl-[3-(2-oxo-oxazolidin-3-yl)-benzyl]-amino}-1H- quinazolin-4-one 440.45 H-36 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(3-methyl-2-oxo-pyrrolidin-1-yl)-benzyl]- amino}-1H-quinazolin-4-one436.51 H-37 —CH₃

2-{[3-(3-Ethyl-2-oxo-pyrrolidin-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 450.54H-38 —OCH₃

2-{[3-(3-Ethyl-2-oxo-pyrrolidin-1-yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy- 1H-quinazolin-4-one 466.54 H-39—CH₃

1-(3-{[(6,7-Dimethoxy-5-methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-pyrrolidine-2,5- dione 436.47 H-40 —OCH₃

1-(3-{[Methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-phenyl)-pyrrolidine-2,5-dione 452.47 H-41 —OCH₃

5,6,7-Trimethoxy-2-{methyl-[3-(2-oxo-imidazolidin-1-yl)-benzyl]-amino}-1H- quinazolin-4-one 439.47 H-42 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (3-methyl-2-oxo-imidazolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 437.50 H-43 —OCH₃

5,6,7-Trimethoxy-2-{methyl-[3-(3-methyl-2-oxo-imidazolidin-1-yl)-benzyl]- amino}-1H-quinazolin-4-one453.49 H-44 —CH₃

2-{[3-(3-Ethyl-2-oxo-imidazolidin-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 451.52H-45 —OCH₃

2-{[3-(3-Ethyl-2-oxo-imidazolidin-1-yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy- 1H-quinazolin-4-one 467.52 H-46—OCH₃

5,6,7-Trimethoxy-2-({3-[3-(2-methoxy-ethyl)-2-oxo-imidazolidin-1-yl]-benzyl}-methyl-amino)-1H-quinazolin-4-one 497.55 H-47 —CH₃

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(1H-tetrazol-5-yl)-benzyl]-amino}-1H- quinazolin-4-one 407.43

Additional compounds prepared according to the procedure of Example H-1through H-3 are shown in Table 11.

Example I-16,7-Dimethoxy-5-methyl-2-[methyl-(4-pyrrolidin-1-yl-pyridin-2-ylmethyl)-amino]-1H-quinazolin-4-one

Step 1

To a 2 N solution of methylamine (6.15 mL, 12.3 mmol) in MeOH was added4-chloro-2-chloromethylpyridine (0.2 g, 1.23 mmol). The resultingsolution was allowed to stir for overnight at rt. After evaporation ofthe solvent, 4-chloro-2-methylaminomethylpyridine was purified by flashcolumn chromatography. The starting material(4-chloro-2-chloromethylpyridine) was prepared according to Tamura etal., Chem. Pharm. Bull., Vol. 48(10) (2000), at pp. 1514-1518.

Step 2

Diisopropylethylamine (0.15 mL, 0.86 mmol) was added to a mixture of2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one (0.2 g, 0.78 mmol) and4-chloro-2-methylaminomethylpyridine (0.13 g, 0.86 mmol) in EtOH (8 mL).The mixture was heated at 90° C. for 5 h. After cooling, the resultingwhite solid was filtered and washed with MeOH to providequinazolino-pyridine compound.

Step 3

4-chloropyridine compound from Step 2 (20 mg, 0.05 mmol) in pyrrolidine(0.5 mL) was heated at 130° C. overnight in a sealed tube. The mixturewas filtered, concentrated, and purified by preparative reversed-phaseHPLC to afford the above Example I-1. ¹H NMR (DMSO-d₆) δ: 2.0 (br, 2H),2.62 (s, 3H), 3.15 (s, 3H), 3.50 (m, 2H), 3.62 (s, 3H), 3.84 (s, 3H),4.90 (s, 2H), 6.72 (m, 1H), 6.79 (dd, 1H), 7.54 (s, 1H), 8.17 (dd, 1H)(as the TFA salt). MS (ES+) m/z 410 (M+H)⁺.

Examples I-2 to I-13

Compounds I-3 through I-8 and 1-13 having the above formula (Io),wherein R⁵, R^(7a) and R^(7b) have the values reported in Table 9, wereprepared following the same or similar method as described for ExampleI-1, replacing the pyrrolidine in step 3 with the desired substituent.The remaining compounds were prepared by condensation of the appropriateamine and carbonyl compounds according to procedures in Abdel-Magid etal. J. Organic Chemistry Vol. 61 (1996), at pp. 3849-3862. TABLE 9 Ex.No R⁵ —R^(7a) —R^(7b) Compound Name MW I-2 —OCH₃

—H 5,6,7-Trimethoxy-2-[(6-{1-[(2- methoxy-ethyl)-methyl-amino]-ethyl}-pyridin-2-ylmethyl)- methyl-amino]-1H-quinazolin- 4-one 471.56I-3 —O—CH₃ —H —Cl 2-[(4-Chloro-pyridin-2- 390.8ylmethyl)-methyl-amino]-5,6,7- trimethoxy-1H-quinazolin-4- one I-4 —OH—H

5-Hydroxy-6,7-Dimethoxy-2- ({4-[(2-methoxy-ethyl)-methyl-amino]-pyridin-2-ylmethyl}- methyl-amino)-5-methyl-1H- quinazolin-4-one429.47 I-5 —CH₃ —H

6,7-Dimethoxy-2-({4-[(2- methoxy-ethyl)-methyl-amino]-pyridin-2-ylmethyl}-methyl- amino)-5-methyl-1H- quinazolin-4-one 427.50I-6 —O—CH₃ —H

5,6,7-trimethoxy-2-({4-[(2- methoxy-ethyl)-methyl-amino]-pyridin-2-ylmethyl}-methyl- amino)-1H-quinazolin-4-one 443.50 I-7 —O—CH₃—H

5,6,7-Trimethoxy-2-{[4-(2- methoxy-ethoxy)-pyridin-2-ylmethyl]-methyl-amino}-1H- quinazolin-4-one 430.46 I-8 —OCH₃ —H OEt2-[(4-Ethoxy-pyridin-2- 400.43 ylmethyl)-methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4- one I-9 —CH₃

—H 6,7-Dimethoxy-5-methyl-2- {methyl-[6-(1-pyrrolidin-1-yl-ethyl)-pyridin-2-ylmethyl]- amino}-1H-quinazolin-4-one 437.54 I-10 —OCH₃

—H 5,6,7-Trimethoxy-2-{methyl- [6-(1-pyrrolidin-1-yl-ethyl)-pyridin-2-ylmethyl]-amino}- 1H-quinazolin-4-one 453.54 I-11 —CH₃

—H 2-{[6-(1-Azetidin-1-yl-ethyl)- pyridin-2-ylmethyl]-methyl-amino}-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 423.51 I-12 —O—CH₃

—H 2-{[6-(1-Azetidin-1-yl-ethyl)- pyridin-2-ylmethyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 439.51 I-13 —CH₃ —H

6,7-Dimethoxy-2-{[4-(2- methoxy-ethoxy)-pyridin-2-ylmethyl]-methyl-amino}-5- methyl-1H-quinazolin-4-one 414.46

Additional compounds prepared according to the procedure of Example I-1are shown in Table 11.

Examples J-1 to J-7

Compounds having the above formula (Ip), wherein R⁵, R¹⁰ and Y—Ar takentogether have the values reported in Table 10, were prepared followingthe same or similar method as described above, e.g., upon couplingcompounds having the desired aryl or heteroaryl groups with2-chloro-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one, or2-chloro-5,6,7-trimethoxy-1H-quinazolin-4-one. TABLE 10 Ex. No R⁵ R¹⁰—Y—Ar MW J-1 —O—CH₃ —CH₃

N,N-Dimethyl-N′-(3-{2-[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- ethyl}-phenyl)-acetamidine 453.54 J-2—CH₃ H

5-[2-(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-ylamino)-propyl]-2-methoxy- benzenesulfonamide 462.52 J-3 —CH₃ H

5-[2-(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-ylamino)-propyl]-2-methoxy-N-(1- dimethylamino-ethylidene)-benzenesulfonamide 531.63 J-4 —CH₃ —CH₃

N′-(3-{2-[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-1- hydroxy-ethyl}-phenyl)-N,N-dimethyl-acetamidine 453.54 J-5 —CH₃ —CH₃

N′-(3-{2-[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]- vinyl}-phenyl)-N,N-dimethyl-acetamidine; 435.53 J-6 —CH₃ —CH₃

2-{[2-(3H-Imidazol-4-yl)-ethyl]- methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 343.39 J-7 —O—CH₃ —CH₃

2-{[2-(3H-Imidazol-4-yl)-ethyl]- methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 359.38 J-8 —CH₃ —CH₃

2-[(1-Benzyl-piperidin-3-yl)- methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 422.53

Example K-1N,N-Dimethyl-N′-(3-{[methyl-(6,7,8-trimethoxy-1,1-dioxo-1,4-dihydro-1l6-benzo[1,2,4]thiadiazin-3-yl)-amino]-methyl}-phenyl)-acetamidine

Step 1: 6,7,8-Trimethoxy benzothiadiazine-3-one-1,1-dioxide

Step 1:6,7,8-Trimethoxy-1,1-dioxo-1,4-dihydro-2H-1lambda*6*-benzo[1,2,4]thiadiazin-3-one

To 45 mL nitroethane was added chlorosulfonylisocyanate (3 mL, 34 mmol).The solution was cooled to −70° C. A solution of trimethoxyaniline (4.5g, 24.5 mmol) in nitroethane (15 mL) was added over 5 minutes. Thetemperature of the solution rose to −64° C. The solution was removedfrom the ice bath and allowed to warm to −5° C. while a heavyprecipitate formed. In one portion, AlCl₃ (5 g, 37.6 mmol) was added.The precipitate went into solution as the temperature rose to 25° C. Theresulting solution was placed in a 110° C. oil bath and stirred for 30min. The resulting mixture was cooled to rt and poured into ice water.The aqueous layer was removed from the resulting black gum, whichcontained some of the desired material, as well as starting material andside products. The aqueous layer was shaken with EtOAc and the layersseparated. The organic layer was evaporated in vacuo and the residuecrystallized from a small amount of EtOAc to yield 6,7,8-trimethoxybenzothiadiazine-3-one-1,1-dioxide. (3.4 g):

mp 220-223 □C; MS (ES+) m/z 289 (M+H); ¹H NMR (DMSO-d6, 2.49)), 3.75 (s,3H), 3.83 (s, 3H), 3.89 (s, 3H), 6.58 (s, 1H), 11 (s, 1H).

Step 2: 6,7,8-trimethoxy-3-chloro-benzothiadiazine-3-1,1-dioxide

To 6,7,8-trimethoxy benzothiadiazine-3-one-1,1-dioxide (2.4 g, 8.3 mmol)was added phosphorous oxychloride (22 mL). The resulting mixture wascooled to 5 □C and N,N-diethylaniline (2.6 mL, 20 mmol) was added. Themixture was allowed to warm to rt, and then heated at 80° C. for 8 h.The solvent was removed by distillation under reduced pressure. Theresulting syrup was poured into ice water. After rapid stirring theprecipitate was filtered. The aqueous mother liquors were extracted withmethylene chloride. The resulting organic layer was dried over Na₂SO₄,the drying agent removed by filtration and the solvent removed underreduced pressure, to afford6,7,8-trimethoxy-3-chloro-benzothiadiazine-3-1,1-dioxide 920 mg. MS(ES+) m/z 307 (M+H); ¹H NMR (DMSO-d6, 2.49)), 3.75 (s, 3H), 3.83 (s,3H), 3.89 (s, 3H), 6.58 (s, 1H), 11 (s, 1H).

Step 3

The chlorobenzothiadiazine dioxide from Step B (130 mg, 0.42 mmol) andN,N-dimethyl-N′-(3-methylaminomethyl-phenyl)-acetamidine (90 mg, 0.43mmol) in EtOH (5 mL) were heated in a sealed tube at 100° C. for 18 h.The mixture was cooled and the suspension filtered. The desired productwas found in both the filter cake and the mother liquors so these werecombined and the solvent removed under reduced pressure. The resultingmaterial was chromatographed on silica gel to yield a partially purifiedfraction which was then further purified by reverse phase HPLC toprovide the above-titled Example K-1. (M+H)⁺ 477.

Example K-2N′-(3-{[(6,7-Dimethoxy-1,1-dioxo-1,4-dihydrobenzo[1,2,4]thiadiazin-3-yl)-methyl-amino]-methyl}-phenyl)-N,N-dimethyl-acetamidine

Step 1:6,7-Dimethoxy-3-(methylaminomethyl-3-nitrophenyl)benzothiadiazine-3-one-1,1-dioxide

A solution of 3-chloro-6,7-dimethoxy-4H-benzo[1,2,4]thiadiazine1,1-dioxide (404 mg, 1.5 mmol), methyl-(3-nitrobenzyl)-aminehydrochloride (400 mg, 2 mmol), DBU (0.25 mL, excess) anddimethoxyethanol (5 mL) was heated at 80° C. 18 h. The solvent wasremoved under reduced pressure. The resulting gum was chromatographed onsilica gel in 3% MeOH in DCM to yield white crystals (250 mg): MS (ES+)m/z 407 (M+H). Substituted 2H-benzo[1,2,4]thiadiazine-1,1-dioxides wereprepared as described in Ref. WO 02/053558 A1. The nitro compound (250mg, 0.6 mmol), 10% Pd/C (32 mg) and EtOH (60 mL) were hydrogenated on aParr apparatus at 45 psi for 18 h. The reaction mixture was thenfiltered under nitrogen through a glass fiber paper and the solventremoved under reduced pressure to yield the aniline as a white solid(210 mg). MS (ES+) m/z 377 (M+H).

Step 2

The aniline from Step 1 (210 mg, 0.56 mmol), dimethylacetamide dimethylacetal-(80 uL, excess) and dimethylacetamide (2 mL) were heated at 80°C. for 18 h. The solvent was removed under reduced pressure. Theresulting gum was dissolved in DCM and chromatographed over silica gelin 4% MeOH in DCM to yield the above-titled Example K-2 as an off whitesolid.

Representative compounds in accordance with the invention are shown inTable 11, together with corresponding melting point or low resolutionMass Spectrum data. TABLE 11 # Structure Systematic Name MP ° C. M + H 1

5,6,7-Trimethoxy-2-[methyl-4- {[methyl-(3,3,3-trifluoro-propyl)-amino]-methyl}-benzyl)-amino]-1H- quinazolin-4-one 97.8-101.9 2

2-{[4-(2-Hydroxy-3-methoxy- propoxy)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 108.1-111.5 3

2-{[3-(3-Hydroxy-2-hydroxymethyl- propoxy)-4-methoxy-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 139.7-146.6 (HCl salt) 4

1-[1-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-ethyl]- 1,3,3-trimethyl-urea 125.9-128.0 5

[1-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-ethyl]- methyl-carbamic acid methyl ester117.9-120.1 6

2-{[3-(3-Hydroxy-2-hydroxymethyl- propoxy)-4-methoxy-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 210.8-215.4 7

2-{[3-(2,3-Dihydroxy-propoxy)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 220-224 (HCl salt) 8

5,6,7-Trimethoxy-2-{[3-((S)-4- methoxy-2-oxo-pyrrolidin-1-yl)-benzyl]-methyl-amino}-1H-quinazolin- 4-one 142.5-147.4 9

(4-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzyl-methyl- carbamic acid 2-methoxy-ethyl ester159.4-160.4 10

N-(4-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzyl)-N- methyl-methanesulfonamide 238-240 11

2-{[3-(4,5-Dihydro-oxazol-2-yl)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 202.3-203.4 12

5,6,7-Trimethoxy-2-{methyl-[4-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-1H- quinazolin-4-one 195.9-197.4 13

2-[(2-Allyl-2,3-dihydro-1H-isoindol-5- ylmethyl)-methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 133.7-136.6 14

2-{[4-(2,3-Dihydroxy-propoxy)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 199.7-201.9 15

2-{[4-(3-Hydroxy-2-hydroxymethyl- propoxy)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 197.5-199 (HCl salt) 16

2-[(3-{2-[(2-Hydroxy-ethyl)-methyl- amino]-ethoxy}-4-methoxy-benzyl)-methyl-amino]-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 144.8-146.2 17

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzyl)-N- methyl-methanesulfonamide 223.9-225.918

5,6,7-Trimethoxy-2-{[2-(2-methoxy- ethyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-methyl-amino}-1H- quinazolin-4-one 133.3-136.6 19

6,7-Dimethoxy-2-{[2-(2-methoxy- ethyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-methyl-amino}-5-methyl- 1H-quinazolin-4-one 173.3-177.9 20

5,6,7-Trimethoxy-2-{[3-(3-methoxy-2-oxo-pyrrolidin-1-yl)-benzyl]-methyl- amino}-1H-quinazolin-4-one90.2-94.7 21

N-Methyl-N-(4-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzyl)-methanesulfonamide 148.8-151 22

2-{[3-(3-Hydroxy-2-oxo-pyrrolidin-1- yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 172.9-175.9 (HCl salt) 23

6,7-Dimethoxy-5-methyl-2-{methyl-[4- (2-methylamino-ethyl)-benzyl]-amino}-1H-quinazolin-4-one 154.6-159.0 24

2-{[3-((S)-4-Hydroxy-2-oxo- pyrrolidin-1-yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 207.5-209.9 25

2-({4-[2-(Ethyl-methyl-amino)- ethoxy]-3-methoxy-benzyl}-methyl-amino)-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 158.1-159.2 26

N-[1-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-ethyl]- N-methyl-methanesulfonamide130.0-133.8 27

2-{[3-((S)-4-Hydroxy-2-oxo- pyrrolidin-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 230.8-232.5 28

2-({4-[2-(Ethyl-methyl-amino)-ethyl]-benzyl}-methyl-amino)-6,7-dimethoxy- 5-methyl-1H-quinazolin-4-one172.4-173.2 29

6,7-Dimethoxy-2-{[3-methoxy-4-(2- methylamino-ethoxy)-benzyl]-methyl-amino}-5-methyl-1H-quinazolin-4-one 168.9-169.8 30

2-[(4-{[Ethyl-(2-hydroxy-ethyl)- amino]-methyl}-benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 142-5 31

2-{[4-(2-Hydroxy-ethoxy)-benzyl]- methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 198.5-199.5 32

2-[(4-{[Ethyl-(2-methoxy-ethyl)- amino]-methyl}-benzyl)-methyl-amino]-5,6,7-trimethoxy-1H- quinazolin-4-one 120-122.4 33

2-[(3-{[(2-Hydroxy-ethyl)-methyl- amino]-methyl}-benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 123.8-125.6 34

5,6,7-Trimethoxy-2-{[3-(3-methoxy-pyrrolidin-1-ylmethyl)-benzyl]-methyl- amino}-1H-quinazolin-4-one89.6-90.2 35

2-({4-[(Ethyl-methyl-amino)-methyl]- benzyl}-methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4-one 172.3-174.4 (HCl salt) 427 36

6,7-Dimethoxy-2-({4-[(2-methoxy- ethylamino)-methyl]-benzyl}-methyl-amino)-5-methyl-1H-quinazolin-4-one 265-268 (HCl salt) 37

6,7-Dimethoxy-2-{[3-(3-methoxy- pyrrolidin-1-ylmethyl)-benzyl]-methyl-amino}-5-methyl-1H-quinazolin-4-one 151.2-152.9 38

6,7-Dimethoxy-5-methyl-2-[methyl-(2- methyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-amino]-1H-quinazolin-4-one 214.9-224.8 39

2-{[3-(4-Hydroxy-piperidin-1- ylmethyl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 97.5-104.7 40

2-{[3-(4-Hydroxy-piperidin-1- ylmethyl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 159.2-159.6 41

2-{[4-(3-Hydroxy-pyrrolidin-1- ylmethyl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 166-169 42

2-[(4-Aminomethyl-benzyl)-methyl- amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 248.2-249.4 (HCl salt) 43

2-[(3-Ethylaminomethyl-benzyl)- methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 133.9-134.7 44

2-{[4-(3-Dimethylamino-propoxy)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one h 191-192.2 (HCl salt) 45

5,6,7-Trimethoxy-2-[methyl-(2-methyl-2,3-dihydro-1H-isoindol-5-ylmethyl)- amino]-1H-quinazolin-4-one165.5-166.5 46

5,6,7-Trimethoxy-2-[methyl-(3- pyrrolidin-1-ylmethyl-benzyl)-amino]-1H-quinazolin-4-one 127.0-129.9 47

2-[(3-Azetidin-1-ylmethyl-benzyl)- methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 131.3-133.1 48

2-{[4-(3-Dimethylamino-propoxy)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 108-111 49

2-{[3-(3-Hydroxy-pyrrolidin-1- ylmethyl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 148.0-149.8 50

2-{[3-(1,3-Dimethyl-imidazolidin-2- ylideneamino)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 200.2-204.4 51

2-{[3-(3-Hydroxy-pyrrolidin-1- ylmethyl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 174.3-176.4 52

N-[1-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-ethyl]- N-methyl-2-methylamino-acetamide118.1-120.8 53

N′-(3-{[(5-Cyano-6,7-dimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N- dimethyl-acetamidine 222.1-226.9 54

6,7-Dimethoxy-2-[(3-{1-[(2-methoxy- ethyl)-methyl-amino]-ethyl}-benzyl)-methyl-amino]-5-methyl-1H- quinazolin-4-one 114.5-116.9 55

6,7-Dimethoxy-5-methyl-2-[methyl-(4- methylaminomethyl-benzyl)-amino]-1H-quinazolin-4-one 264-268 (HCl salt) 56

2-[(3-Dimethylaminomethyl-benzyl)- methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 174.9-176.0 57

2-[(3-Dimethylaminomethyl-benzyl)- methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 110.0-113.1 58

1,5-Dimethyl-3-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-imidazolidine-2,4-dione179.1-179.9 59

1-Methyl-3-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-imidazolidine-2,4-dione130.3-137.0 60

3-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-1- methyl-imidazolidine-2,4-dione209.3-210.8 61

2-{[3-(1-Dimethylamino-ethyl)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 137.0-140.1 62

2-{[3-(1-Dimethylamino-ethyl)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 122.6-125.5 63

5,6,7-Trimethoxy-2-{methyl-[3-(1- methylamino-ethyl)-benzyl]-amino}-1H-quinazolin-4-one 131.8-134.4 64

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (1-methylamino-ethyl)-benzyl]-amino}-1H-quinazolin-4-one 161.6-164.1 65

1-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-3- methyl-pyrrolidine-2,5-dione217.8-219.2 66

2-[(3-Cyclopropylaminomethyl- benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 144.5-147.6 67

2-{[3-(Isopropylamino-methyl)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 143.3-144.4 68

6,7-Dimethoxy-5-methyl-2-(methyl-{3- [(methyl-propyl-amino)-methyl]-benzyl}-amino)-1H-quinazolin-4-one 128.1-129.1 69

6,7-Dimethoxy-5-methyl-2-(3- methylaminomethyl-benzylamino)-1H-quinazolin-4-one 142.5-142.9 70

N-(3-{[(6,7-Dimethoxy-4-oxo-1,4- dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N-dimethyl- acetamidine 221.8-223 71

2-({3-[(Ethyl-methyl-amino)-methyl]-benzyl}-methyl-amino)-6,7-dimethoxy- 5-methyl-1H-quinazolin-4-one146.7-150.8 72

N′-{3-[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-ylamino)-methyl]-phenyl}-N,N- dimethyl-acetamidine 173-175 73

5,6,7-Trimethoxy-2-[4-(4-methoxy- pyridin-2-yl)-piperazin-1-yl]-1H-quinazolin-4-one 229-231 74

N-(3-{[(7-Chloro-6-methoxy-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N-dimethyl- acetamidine 185.4-191.9 75

5,6,7-Trimethoxy-2-{methyl-[3-(3- methyl-2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 156.4-162.0 76

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (2-oxo-imidazolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 265.0-266.0 77

6,7-Dimethoxy-2-({3-[(2-methoxy- ethylamino)-methyl]-benzyl}-methyl-amino)-5-methyl-1H-quinazolin-4-one 150.0-152.1 78

5,6,7-Trimethoxy-2-{methyl-[3-(1- methyl-piperidin-4-yl)-benzyl]-amino}-1H-quinazolin-4-one 181.5-189.4 79

6,7-Dimethoxy-2-[methyl-(3- pyrrolidin-1-yl-benzyl)-amino]-1H-quinazolin-4-one 220-223 80

2-[Benzyl-(1-benzyl-piperidin-4-yl)- amino]-6,7-dimethoxy-1H-quinazolin-4-one 485 81

6,7-Dimethoxy-2-[methyl-(6-methyl- pyridin-2-ylmethyl)-amino]-1H-quinazolin-4-one 341 82

2-{[2-(1H-Indol-3-yl)-ethyl]-methyl- amino}-6,7-dimethoxy-1H-quinazolin-4-one 379 83

6,7-Dimethoxy-2-{methyl-[3-(4- methyl-piperazin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 424 84

6,7-Dimethoxy-2-[2-(4-methyl- piperazin-1-yl)-benzylamino]-1H-quinazolin-4-one 85

2-(Benzyl-isopropyl-amino)-6,7- dimethoxy-1H-quinazolin-4-one 168-170.5354 86

N′-(3-{[(6,7-Dimethoxy-4-oxo-1,4- dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N-dimethyl- formamidine 242-245 (HCl salt)395.4 M⁺ 87

2-{[3-(4,5-Dihydro-3H-pyrrol-2- ylamino)-benzyl]-methyl-amino}-6,7-dimethoxy-1H-quinazolin-4-one 211-14 407.5 M⁺ 88

N-(3-{[(6,7-Dimethoxy-4-oxo-1,4- dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-acetamidine 263-66 (HBr salt) 381.4 M⁺ 89

2-{[3-(4,5-Dihydro-1H-imidazol-2- ylamino)-benzyl]-methyl-amino}-6,7-dimethoxy-1H-quinazolin-4-one 163.8-176.9 409 90

2-{[3-(4,4-Dimethyl-4,5-dihydro- imidazol-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-1H-quinazolin-4-one 240-244 422 91

N′-(3-{2-[(6,7-Dimethoxy-4-oxo-1,4- dihydro-quinazolin-2-yl)-methyl-amino]-ethyl}-phenyl)-N,N-dimethyl- acetamidine 135-138.1 423.5 M⁺ 92

6,7-Dimethoxy-2-(methyl-{2-[3- (pyrimidin-2-ylamino)-phenyl]-ethyl}-amino)-1H-quinazolin-4-one 433 93

2-[(2-{3-[(1H-Imidazol-2-ylmethyl)- amino]-phenyl}-ethyl)-methyl-amino]-6,7-dimethoxy-1H-quinazolin-4-one 435 94

2-{[2-(3,4-Dimethoxy-phenyl)-ethyl]- methyl-amino}-6,7-dimethoxy-1H-quinazolin-4-one 400 95

2-[(3-Amino-benzyl)-methyl-amino]- 6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 268-269.5 96

3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzonitrile 279.9-281.5 (TFA salt) 365 97

2-[Benzyl-(2-dimethylamino-ethyl)- amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 397 98

2-[(3-Bromo-benzyl)-methyl-amino]- 6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 232.9-234 419 99

2-[(3-Bromo-benzyl)-methyl-amino]- 5,6,7-trimethoxy-1H-quinazolin-4-one435 100

2-[(2-Fluoro-benzyl)-(2-hydroxy- ethyl)-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 388 101

3-{[Methyl-(5,6,7-trimethoxy-4-oxo- 1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-benzonitrile 381 102

6,7-Dimethoxy-5-methyl-2-[methyl-(3- methylamino-benzyl)-amino]-1H-quinazolin-4-one 195.9-197.9 368.4 M⁺ 103

2-[(3-Amino-benzyl)-methyl-amino]- 5,6,7-trimethoxy-1H-quinazolin-4-one225-226.5 370.4 M⁺ 104

2-[(2-Amino-benzyl)-methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one >300 (decomp) (HCl Salt) 370.4 M⁺105

6,7-Dimethoxy-5-methyl-2-[methyl-(3- methylaminomethyl-benzyl)-amino]-1H-quinazolin-4-one 179.0-181.3 383 106

2-[(3-Aminomethyl-benzyl)-methyl- amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 369 107

(3-{[Methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-phenyl)-acetonitrile149.5-153.3 395 108

2-[(3-Hydroxymethyl-benzyl)-methyl- amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 386 109

5-Hydroxy-2-[(3-hydroxymethyl- benzyl)-methyl-amino]-6,7-dimethoxy-1H-quinazolin-4-one 372 110

5,6,7-Trimethoxy-2-[methyl-(3- morpholin-4-ylmethyl-benzyl)-amino]-1H-quinazolin-4-one 160.0-162.1 455 111

5,6,7-Trimethoxy-2-[methyl-(3- methylaminomethyl-benzyl)-amino]-1H-quinazolin-4-one 124.9-127.6 398.5 M⁺ 112

2-[Ethyl-(3-methylaminomethyl- benzyl)-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 159.3-164.1 396.5 M⁺ 113

2-[(3-Ethylaminomethyl-benzyl)- methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 158.2-158.9 396.5 M⁺ 114

2-({3-[(Ethyl-methyl-amino)-methyl]- benzyl}-methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4-one 106.5-108.9 426.5 M⁺ 115

6,7-Dimethoxy-5-methyl-2-(methyl-{3-[(2,2,2-trifluoro-ethylamino)-methyl]-benzyl}-amino)-1H-quinazolin-4-one 180.4-181.5 450.5 M⁺ 116

2-[(3-{[(2-Hydroxy-ethyl)-methyl- amino]-methyl}-benzyl)-methyl-amino]-5,6,7-trimethoxy-1H- quinazolin-4-one 169.0-171.9 (HCl Salt) 443117

5,6,7-Trimethoxy-2-[(3-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzyl)- methyl-amino]-1H-quinazolin-4-one162.9-164.5 (bishydro- chloride salt) 457 118

2-[(3-{[Ethyl-(2-methoxy-ethyl)- amino]-methyl}-benzyl)-methyl-amino]-5,6,7-trimethoxy-1H- quinazolin-4-one 164.5-166.0 (HCl Salt)470.6 M⁺ 119

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzyl)-2- methoxy-N-methyl-acetamide 150.0-151.2454.5 M⁺ 120

2-Methoxy-N-methyl-N-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzyl)-acetamide 115-117 470.5 M⁺ 121

2-[(3-{[Ethyl-(2-methoxy-ethyl)- amino]-methyl}-benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 121.8-122.3 454.6 M⁺122

6,7-Dimethoxy-5-methyl-2-[methyl-(3-pyrrolidin-1-ylmethyl-benzyl)-amino]- 1H-quinazolin-4-one 163.9-164.5422.5 M⁺ 123

5-Hydroxy-6,7-dimethoxy-2-{methyl- [3-(1-methyl-4,5-dihydro-1H-imidazol-2-ylmethyl)-benzyl]-amino}-1H- quinazolin-4-one 438 124

5,6,7-Trimethoxy-2-{methyl-[3-(1- methyl-4,5-dihydro-1H-imidazol-2-ylmethyl)-benzyl]-amino}-1H- quinazolin-4-one 452 125

5-Hydroxy-2-{[3-(1-isopropyl-4,5- dihydro-1H-imidazol-2-ylmethyl)-benzyl]-methyl-amino}-6,7-dimethoxy- 1H-quinazolin-4-one 466 126

2-{[3-(1-Isopropyl-4,5-dihydro-1H- imidazol-2-ylmethyl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 480 127

5,6,7-Trimethoxy-2-{methyl-[3-(1- methyl-piperidin-4-ylmethyl)-benzyl]-amino}-1H-quinazolin-4-one 175-195 (HCl Salt) 466.6 M⁺ 128

2-[(3-Methanesulfonyl-benzyl)-methyl- amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 269.5-271.5 417.5 M+ 129

2-[(3-Methanesulfonyl-benzyl)-methyl- amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 231.5-232.9 433.5 M+ 130

N,N-Dimethyl-3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzenesulfonamide 199.9 to 204.0 462.5M+ 131

3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-N-(2-methoxy-ethyl)- benzenesulfonamide 163.0-164.9 476.6M+ 132

N-(2-Methoxy-ethyl)-3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzenesulfonamide 176.9-179.1 492.6 M+133

3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-N-(3-methoxy- propyl)-benzenesulfonamide 169.0-171.9490.6 M+ 134

3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzoic acid 283.1-286.2 383.4 M+ 135

3-{[Methyl-(5,6,7-trimethoxy-4-oxo- 1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-benzoic acid 400 136

3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-N-methyl-benzamide 243.3-245.1 396.4 M⁺ 137

N-Methyl-3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzamide 217.9-219.1 412.4 M⁺ 138

N-(2-Dimethylamino-ethyl)-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-benzamide 470 139

N-(2-Dimethylamino-ethyl)-N-methyl- 3-{[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-benzamide 484 140

N-(3-Dimethylamino-propyl)-N- methyl-3-{[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)- amino]-methyl}-benzamide 498 141

N-(2-Hydroxy-ethyl)-3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzamide 443 142

N-(2-Hydroxy-propyl)-3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzamide 457 143

N-(2-Hydroxy-ethyl)-N-methyl-3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-benzamide 457 144

N-(2-Methoxy-ethyl)-3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzamide 457 145

N-(3-Methoxy-propyl)-3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzamide 471 146

N-Cyanomethyl-3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzamide 438 147

3-{[Methyl-(5,6,7-trimethoxy-4-oxo- 1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-N-(tetrahydro-furan-2- ylmethyl)-benzamide 483 148

N-Furan-2-ylmethyl-3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- benzamide 479 149

3-{[Methyl-(5,6,7-trimethoxy-4-oxo- 1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-N-(2-morpholin-4-yl-ethyl)- benzamide 512 150

2-{[3-(4-Hydroxymethyl-piperidine-1- carbonyl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 497 151

2-{[3-(2-Hydroxy-ethoxy)-benzyl]- methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 146.0-147.5 416 152

2-[(3-Methanesulfinylmethoxy- benzyl)-methyl-amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 191.0-193.5 432 153

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (pyrimidin-2-yloxy)-benzyl]-amino}-1H-quinazolin-4-one 224.0-227.8 434 154

2-[(3-Hydroxy-benzyl)-methyl-amino]- 6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 252.9-254.35 355.4 M+ 155

2-[(3-Hydroxy-benzyl)-methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 212.3-215.1 371.4 M+ 156

2-[(3-Methanesulfonylmethoxy- benzyl)-methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 183.9-185.4 463.5 M+ 157

(3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenoxy)-acetic acid >300 413.4 M+ 158

(3-{[Methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-phenoxy)-acetic acid >300429.4 M+ 159

2-{[3-(2-Hydroxy-ethoxy)-benzyl]- methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 180.5-183.1 399.4 M+ 160

6,7-Dimethoxy-2-{[3-(2-methoxy- ethoxy)-benzyl]-methyl-amino}-5-methyl-1H-quinazolin-4-one 176.6-177.9 413.5 M+ 161

5,6,7-Trimethoxy-2-{[3-(2-methoxy- ethoxy)-benzyl]-methyl-amino}-1H-quinazolin-4-one 144.8-145.9 429.5 M+ 162

6,7-Dimethoxy-2-{[3-(3-methoxy- propoxy)-benzyl]-methyl-amino}-5-methyl-1H-quinazolin-4-one 150.1-152.0 427.5 M+ 163

5,6,7-Trimethoxy-2-{[3-(3-methoxy- propoxy)-benzyl]-methyl-amino}-1H-quinazolin-4-one 147.5-149.1 443.5 M+ 164

2-{[3-(2-Dimethylamino-ethoxy)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 137.9-141.9 426.5 M+ 165

2-{[3-(2-Ethylamino-ethoxy)-benzyl]- methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 264.6-266.5 426.5 M+ 166

5,6,7-Trimethoxy-2-{methyl-[3- (pyrimidin-2-yloxy)-benzyl]-amino}-1H-quinazolin-4-one 191-192.9 449.5 M+ 167

N′-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N- dimethyl-acetamidine 174.4-174.8 424168

N-(3-{[(5-Isopropyl-6,7-dimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)- methanesulfonamide 215-17 169

N′-(3-{[(6,7-dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N- dimethylsulfamide 195.3-199.0 170

N-(3-{[(6,7-dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)- N,N′,N′-trimethylsulfamide 160.0-161.7171

N,N-Dimethyl-N′-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-sulfamide 176.5-179.7 172

N,N,N′-Trimethyl-N′-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-sulfamide 170.3-172.3 173

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)- acetamide 250-2 174

N-(3-{[Methyl-(5,6,7-trimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-phenyl)-acetamide 166.5-172.9 (HCl Salt) 175

N-(4-Chloro-3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-acetamide 447, M+ 176

1,1-Dimethyl-3-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-urea 442 177

(3-{[Methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-phenyl)-carbamic acidmethyl ester 230.9-232.1 178

(3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-methyl- carbamic acid methyl ester 191.9-194.1179

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N- methyl-2-oxo-propionamide 198.9-201.9180

3-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-1,1- dimethyl-urea 131.5-168.0 181

N-Methoxy-N′-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl-amino]-methyl}- phenyl)-urea 165-7 182

2-{[3-(2-Hydroxy-ethylamino)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 60.5-61.4 183

5-Hydroxy-2-({3-[(3-hydroxy-propyl)- methyl-amino]-benzyl}-methyl-amino)-6,7-dimethoxy-1H-quinazolin- 4-one 429 184

2-{[3-(3-Hydroxy-propylamino)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 47-48.5 185

5,6,7-Trimethoxy-2-{[3-(2-methoxy- ethylamino)-benzyl]-methyl-amino}-1H-quinazolin-4-one 178.9-179.9 (HCl Salt) 186

5,6,7-Trimethoxy-2-({3-[(2-methoxy- ethyl)-methyl-amino]-benzyl}-methyl-amino)-1H-quinazolin-4-one 179.3-181.2 (HCl Salt) 187

2-({3-[(3-Hydroxy-propyl)-methyl- amino]-benzyl}-methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4-one 156-157.2 (HCl Salt) 188

5,6,7-Trimethoxy-2-{[3-(3-methoxy- propylamino)-benzyl]-methyl-amino}-1H-quinazolin-4-one 207.0-209.1 (HCl Salt) 189

5,6,7-Trimethoxy-2-({3-[(3-methoxy- propyl)-methyl-amino]-benzyl}-methyl-amino)-1H-quinazolin-4-one bi 166.7-168.1 (HCl Salt) 190

2-({3-[Bis-(2-hydroxy-ethyl)-amino]- benzyl}-methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4-one 138.1-141 191

N-[2-(3-{1-[(6,7-Dimethoxy-5-methyl- 4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-ethyl}-phenylamino)- ethyl]-acetamide 220.6-222.4 192

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)- acetamidine 155-58 193

N-(3-{[Methyl-(5,6,7-trimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-phenyl)-acetamidine 412 194

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N′- dimethyl-acetamidine 181.2-186.6 195

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N′- methyl-acetamidine 233.1-233.9 196

N-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N- dimethyl-formamidine 185-86 197

N,N-Dimethyl-N′-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-acetamidine 199-201 198

N,N-Dimethyl-N′-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-isobutyramidine 148-50 199

N′-(3-{[(5-Ethyl-6,7-dimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N-dimethyl- acetamidine 224.6-225.5 200

N′-(3-{[(5-Isopropyl-6,7-dimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N- dimethyl-acetamidine 235.6-236.5 201

N′-(3-{[(5-Hydroxy-6,7-dimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N- dimethyl-acetamidine 426 202

3-Methoxy-N,N-dimethyl-N′-(3- {[methyl-(5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]- methyl}-phenyl)-propionamidine 145 203

N,N-Dimethyl-N′-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-cyclobutanecarboxamidine164.2-165.7 204

2-{[3-(Imidazolidin-2-ylideneamino)-benzyl]-methyl-amino}-6,7-dimethoxy- 5-methyl-1H-quinazolin-4-one141.3-144.7 205

5,6,7-Trimethoxy-2-(methyl-{3-[1- methyl-pyrrolidin-(2Z)-ylideneamino]-benzyl}-amino)-1H-quinazolin-4-one 130-133 206

2-{[2-Chloro-5-(1,3-dimethyl- imidazolidin-2-ylideneamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H- quinazolin-4-one 501, M+ 207

2-{[3-(1,3-dimethyl-imidazolidin-2- ylideneamino)-benzyl]-methyl-amino}-5-ethyl-6,7-dimethoxy-1H-quinazolin- 4-one 212.5-219.9 (PF₆ salt) 208

2-{[3-(4,5-Dihydro-3H-pyrrol-2- ylamino)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 175.4-177.2 209

2-{[3-(4,5-Dihydro-3H-pyrrol-2- ylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 207-209 210

5,6,7-Trimethoxy-2-{methyl-[3-(2-oxo-tetrahydro-furan-3-ylamino)-benzyl]- amino}-1H-quinazolin-4-one 455 211

2-({5-[(4,5-Dihydro-3H-pyrrol-2-yl)- methyl-amino]-2-fluoro-benzyl}-methyl-amino)-5-hydroxy-6,7- dimethoxy-1H-quinazolin-4-one 264.9-267 212

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (pyrimidin-2-ylamino)-benzyl]-amino}-1H-quinazolin-4-one 433 213

5,6,7-Trimethoxy-2-{methyl-[3- (pyrimidin-2-ylamino)-benzyl]-amino}-1H-quinazolin-4-one 190.3-191.1 214

2-{[3-(2-Chloro-pyrimidin-4-ylamino)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 205.9-210.1 215

2-{[3-(4-Chloro-pyrimidin-2-ylamino)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 128.9-133.4 216

2-{[3-(2-Chloro-pyrimidin-4-ylamino)-benzyl]-methyl-amino}-6,7-dimethoxy- 5-methyl-1H-quinazolin-4-one 467217

2-{[3-(2-Chloro-5-methyl-pyrimidin-4- ylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 225.9-227.0 218

2-{[3-(2-Chloro-6-methyl-pyrimidin-4- ylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 185.5-187.1 219

2-{[3-(4-Chloro-6-methyl-pyrimidin-2- ylamino)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 191.3-192.8 220

2-({3-[(1H-Imidazol-2-ylmethyl)- amino]-benzyl}-methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4-one 125.0-131.0 221

N′-(3-{[(5-Fluoro-6,7-dimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)-N,N- dimethyl-acetamidine 199.9-201.9 222

5,6,7-Trimethoxy-2-{methyl-[3-(2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-1H- quinazolin-4-one 165.5-166.5 439 223

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(1-methyl-4,5-dihydro-1H-imidazol-2- yl)-benzyl]-amino}-1H-quinazolin-4-one 145-148 422 224

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (1-methyl-piperidin-4-yl)-benzyl]-amino}-1H-quinazolin-4-one 155.7-158.1 437 225

6,7-Dimethoxy-5-methyl-2-[methyl-(3- pyrrolidin-1-yl-benzyl)-amino]-1H-quinazolin-4-one 409 226

5,6,7-Trimethoxy-2-[methyl-(3- pyrrolidin-1-yl-benzyl)-amino]-1H-quinazolin-4-one 425 227

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(2-methyl-4,5-dihydro-imidazol-1-yl)- benzyl]-amino}-1H-quinazolin-4-one177-180 228

2-{[3-(4,4-Dimethyl-4,5-dihydro- imidazol-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 437 229

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(2,4,4-trimethyl-4,5-dihydro-imidazol-1-yl)-benzyl]-amino}-1H-quinazolin-4- one 450 230

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (4-methyl-imidazol-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 245-249.5 231

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (2-methyl-imidazol-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 420 232

6,7-Dimethoxy-5-methyl-2-[methyl-(3- pyrazol-1-yl-benzyl)-amino]-1H-quinazolin-4-one 220.8-224.1 233

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (3-methyl-pyrazol-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 220-223.5 234

2-{[3-(3,5-Dimethyl-pyrazol-1-yl)- benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 434 235

6,7-Dimethoxy-5-methyl-2-[methyl-(3- pyrrolidin-2-yl-benzyl)-amino]-1H-quinazolin-4-one 409 236

5,6,7-Trimethoxy-2-[methyl-(3- pyrrolidin-3-yl-benzyl)-amino]-1H-quinazolin-4-one 425 237

6,7-Dimethoxy-5-methyl-2-{methyl-[4-(1-methyl-4,5-dihydro-1H-imidazol-2- yl)-benzyl]-amino}-1H-quinazolin-4-one 179-181 238

5,6,7-Trimethoxy-2-{methyl-[3-(1- methyl-4,5-dihydro-1H-imidazol-2-yl)-benzyl]-amino}-1H-quinazolin-4-one 438, M+ 239

2-{[3-(1-Ethyl-4,5-dihydro-1H- imidazol-2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 436 240

2-{[3-(1-Ethyl-4,5-dihydro-1H- imidazol-2-yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 452 241

2-{[3-(1-Isopropyl-4,5-dihydro-1H- imidazol-2-yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 466 242

2-{[4-(1-Isopropyl-4,5-dihydro-1H- imidazol-2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 450 243

5-Hydroxy-2-{[3-(1-isopropyl-4,5- dihydro-1H-imidazol-2-yl)-benzyl]-methyl-amino}-6,7-dimethoxy-1H- quinazolin-4-one 453 244

2-({3-[1-(2-Hydroxy-ethyl)-4,5- dihydro-1H-imidazol-2-yl]-benzyl}-methyl-amino)-6,7-dimethoxy-5- methyl-1H-quinazolin-4-one 253-254.9 245

2-({3-[1-(2-Hydroxy-ethyl)-4,5- dihydro-1H-imidazol-2-yl]-benzyl}-methyl-amino)-5,6,7-trimethoxy-1H- quinazolin-4-one 106.1-116.6 (TFASalt) 246

6,7-Dimethoxy-2-({3-[1-(2-methoxy- ethyl)-4,5-dihydro-1H-imidazol-2-yl]-benzyl}-methyl-amino)-5-methyl-1H- quinazolin-4-one 161-164.4 247

5,6,7-Trimethoxy-2-({3-[1-(2- methoxy-ethyl)-4,5-dihydro-1H-imidazol-2-yl]-benzyl}-methyl-amino)- 1H-quinazolin-4-one 483 248

2-{[3-(1H-Imidazol-2-yl)-benzyl]- methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 255.5-258.9 249

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(1-methyl-1H-imidazol-2-yl)-benzyl]- amino}-1H-quinazolin-4-one179-182.1 250

2-({3-[1-(2-Hydroxy-ethyl)-1H- imidazol-2-yl]-benzyl}-methyl-amino)-6,7-dimethoxy-5-methyl-1H- quinazolin-4-one 451 251

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 210.9-212.1 252

2-{[3-(1,1-Dioxo-1λ6-isothiazolidin-2- yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 226.0-228.5 253

{[3-(1,1-Dioxo-1λ6-isothiazolidin-2- yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 181.1-183.5 254

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (2-oxo-oxazolidin-3-yl)-benzyl]-amino}-1H-quinazolin-4-one 254.8-257.1 255

5,6,7-Trimethoxy-2-{methyl-[3-(2-oxo-oxazolidin-3-yl)-benzyl]-amino}-1H- quinazolin-4-one 226.0-229.5 256

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (3-methyl-2-oxo-pyrrolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 210.8-211.6 257

2-{[3-(3-Ethyl-2-oxo-pyrrolidin-1-yl)-benzyl]-methyl-amino}-6,7-dimethoxy- 5-methyl-1H-quinazolin-4-one200.1-202.1 258

2-{[3-(3-Ethyl-2-oxo-pyrrolidin-1-yl)- benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 467 259

1-(3-{[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-phenyl)- pyrrolidine-2,5-dione 198.6-199.8 260

1-(3-{[Methyl-(5,6,7-trimethoxy-4- oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}-phenyl)-pyrrolidine- 2,5-dione 125.5-128.5 261

5,6,7-Trimethoxy-2-{methyl-[3-(2-oxo-imidazolidin-1-yl)-benzyl]-amino}-1H- quinazolin-4-one 130.3-133.0 262

6,7-Dimethoxy-5-methyl-2-{methyl-[3- (3-methyl-2-oxo-imidazolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 230.0-230.5 263

5,6,7-Trimethoxy-2-{methyl-[3-(3- methyl-2-oxo-imidazolidin-1-yl)-benzyl]-amino}-1H-quinazolin-4-one 205.4-207.8 264

2-{[3-(3-Ethyl-2-oxo-imidazolidin-1- yl)-benzyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 201.4-207.4 265

2-{[3-(3-Ethyl-2-oxo-imidazolidin-1- yl)-benzyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 200.3-200.9 266

5,6,7-Trimethoxy-2-({3-[3-(2- methoxy-ethyl)-2-oxo-imidazolidin-1-yl]-benzyl}-methyl-amino)-1H- quinazolin-4-one 199.5-202.1 267

6,7-Dimethoxy-5-methyl-2-{methyl-[3-(1H-tetrazol-5-yl)-benzyl]-amino}-1H- quinazolin-4-one 408 268

6,7-Dimethoxy-5-methyl-2-[methyl-(4-pyrrolidin-1-yl-pyridin-2-ylmethyl)- amino]-1H-quinazolin-4-one 410 269

5,6,7-Trimethoxy-2-[(6-{1-[(2- methoxy-ethyl)-methyl-amino]-ethyl}-pyridin-2-ylmethyl)-methyl-amino]- 1H-quinazolin-4-one 472 270

2-[(4-Chloro-pyridin-2-ylmethyl)- methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 391, 393 271

5-Hydroxy-6,7-dimethoxy-2-({4-[(2- methoxy-ethyl)-methyl-amino]-pyridin-2-ylmethyl}-methyl-amino)-1H- quinazolin-4-one 430.1 272

6,7-Dimethoxy-2-({4-[(2-methoxy- ethyl)-methyl-amino]-pyridin-2-ylmethyl}-methyl-amino)-5-methyl- 1H-quinazolin-4-one 428 273

5,6,7-Trimethoxy-2-{[4-(2-methoxy- ethoxy)-pyridin-2-ylmethyl]-methyl-amino}-1H-quinazolin-4-one 431 274

2-[(4-Ethoxy-pyridin-2-ylmethyl)- methyl-amino]-5,6,7-trimethoxy-1H-quinazolin-4-one 401 275

6,7-Dimethoxy-5-methyl-2-{methyl-[6-(1-pyrrolidin-1-yl-ethyl)-pyridin-2-ylmethyl]-amino}-1H-quinazolin-4-one 75.4-85.6 276

5,6,7-Trimethoxy-2-{methyl-[6-(1- pyrrolidin-1-yl-ethyl)-pyridin-2-ylmethyl]-amino}-1H-quinazolin-4-one 454 277

2-{[6-(1-Azetidin-1-yl-ethyl)-pyridin- 2-ylmethyl]-methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one 424 278

2-{[6-(1-Azetidin-1-yl-ethyl)-pyridin- 2-ylmethyl]-methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 70.8-78.8 279

6,7-Dimethoxy-2-{[4-(2-methoxy- ethoxy)-pyridin-2-ylmethyl]-methyl-amino}-5-methyl-1H-quinazolin-4-one 415 280

N,N-Dimethyl-N′-(3-{2-[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-ethyl}- phenyl)-acetamidine 454 281

5-[2-(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-ylamino)-propyl]-2-methoxy- benzenesulfonamide 463 282

5-[2-(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-ylamino)-propyl]-N-[1-dimethylamino-eth-(E)- ylidene]-2-methoxy-benzenesulfonamide 532 283

N′-(3-{2-[(6,7-Dimethoxy-5-methyl-4- oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-1-hydroxy-ethyl}- phenyl)-N,N-dimethyl-acetamidine 455 284

N′-(3-{(E)-2-[(6,7-Dimethoxy-5- methyl-4-oxo-1,4-dihydro-quinazolin-2-yl)-methyl-amino]-vinyl}-phenyl)- N,N-dimethyl-acetamidine 436 285

2-{[2-(3H-Imidazol-4-yl)-ethyl]- methyl-amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 344 286

2-{[2-(3H-Imidazol-4-yl)-ethyl]- methyl-amino}-5,6,7-trimethoxy-1H-quinazolin-4-one 360 287

2-[(1-Benzyl-piperidin-3-yl)-methyl- amino]-6,7-dimethoxy-5-methyl-1H-quinazolin-4-one 423 288

N,N-Dimethyl-N′-(3-{[methyl-(6,7,8-trimethoxy-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-amino]- methyl}-phenyl)-acetamidine 477 289

N′-(3-{[(6,7-Dimethoxy-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3- yl)-methyl-amino]-methyl}-phenyl)-N,N-dimethyl-acetamidine 446 290

6,7-Dimethoxy-2-[3-(4-methyl- piperazin-1-yl)-benzylamino]-1H-quinazolin-4-one 410 291

6,7-Dimethoxy-5-methyl-2-[2-(4- methyl-piperazin-1-yl)-benzylamino)-1H-quinazolin-4-one 424 292

N-Methyl-N-[1-(3-{[methyl-(5,6,7- trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-ethyl]-methanesulfonamide171.0-172.4 293

1,1,3-Trimethyl-3-[1-(3-{[methyl- (5,6,7-trimethoxy-4-oxo-1,4-dihydro-quinazolin-2-yl)-amino]-methyl}- phenyl)-ethyl]-urea 68-70 294

(3-{[(6,7-Dimethoxy-5-methyl-4-oxo- 1,4-dihydro-quinazolin-2-yl)-methyl-amino]-methyl}-benzyl)-methyl- carbamic acid 2-methoxy-ethyl ester145.8-146.9

Table 11 Assay Examples Example L-1

The potency and selectivity of the inventive compounds as α1A/Bantagonists was determined with CHO-K1 cells expressing adrenoceptorsubtype α1A-215, α1B or α1D by measuring cAMP accumulation usingAlphaScreen.

Cell preparation was accomplished by culturing CHO-α1 cloned cells inHam's F12 nutrient media supplemented with 10% FBS and G418 (25 mg/mL),harvested at 80% confluence, washed with warmed PBS ×2, and detachedwith versene for 5 min. at 37° C. The cultured cells were thenresuspended in 40 mL of stimulation buffer (HBSS with 5 mM hepes, 0.1%BSA) and centrifuged at 500-100 rpm for 5 min. The obtained pellet wasresuspended in stimulation buffer (with 0.5M IBMX), and the cells werecounted. Cells were diluted to the desired number of cells/mL (α1A at3×10⁶/mL, α1B 15×10⁶/mL, and α1D 20×10⁶/mL).

The compounds being tested were diluted in stimulation buffer (with 0.5MIBMX), from 10⁻⁵ to 10⁻¹¹ (final) dilution, 11 points. 5 μl of eachcompound was dispensed to 96 well ½ area plates in triplicate. 5 μl ofstimulation buffer was dispensed to a norepinephrine (NE) plate. 10 μlof cells were added with anti-cAMP Acceptor beads in stimulation bufferto each plate and incubated for 15 min. at RT (in dark or covered withblack plate). Then 5 μl of NE was added to the antagonist plates, at 1μl for α1A and 1B and at 100 nM for α1D, and then 5 μl serial dilutionof NE was added to NE plate. Plates were incubated for 30 min. at RT (indark or covered with black plate) and 10 μl Donor beads+biotin-cAMP inlysis buffer (5 mM Hepes, 0.54% Tween-20, 0.1% BSA) was added. Plateswere incubated for 3 h. at RT with gentle shaking (in dark or coveredwith black plate). Plates were read on an AlphaScreen Fusion analyzer,using reagent pursuant to AlphaSreen cAMP detection kit (PerkinElmerCat#6760600).

Reference compounds norepinephrine, prazosin and vehicle were run inevery experiment. In each plate, on column 12, A-D were loaded with onlycells to define total count and E-H were loaded with NE 1 μM, (total—NE1 μM), to define 100% NE activity. The values determined for eachexperimental well on the plate were divided by (total count—NE 1 μM), todetermine % of NE activity. All data was plotted using non-liner curvefitting by GraphPad Prism to get pEC₅₀ (pEC₅₀ being the negativelogarithm of EC₅₀, i.e., the molar concentration of an agonist whichproduces 50% of the maximum possible response for that agonist) fornorepinephrine and pKb (wherein Kb is the equilibrium dissociation for acompetitive antagonist, determined in a functional assay, and beingequal to the concentration of antagonist which would occupy 50% of thereceptors at equilibrium, units=mol 1⁻, and pKb is the negativelogarithm of Kb) for prazosin and tested compounds. (AlphaScreen cAMPDetection Kit from PerkinElmer Life Sciences).

Example L-2 Example [³H]prazosin Binding (Alpha1-Adrenoceptor) Assay

Alpha1A, alpha1B, and alpha1D adrenoceptor transfected CHO-K¹ cells,prepared using the methods described by Chang et al., FEBS Lett. 1998,422:279-283, were grown to confluence in T-162 tissue culture flasks inHam's F-12 culture medium supplemented with 10% fetal bovine serum,geneticin (150 μg/mL) and streptomycin/penicillin (30 μg/mL/30 μg/mL) at37° C. in 7% CO₂. Cells were harvested by incubating withphosphate-buffered saline (PBS) containing 30 μM EDTA for 5-10 min at37° C. Cells were pelleted by centrifuging at 500×g for 5 min, and thepelleted cells were homogenized (Polytron homogenizer) in 10 vols (w/v)of 50 mM Tris, 1 mM EDTA, (homogenisation buffer, pH 7.4 at 4° C.). Thehomogenate was centrifuged at 45,000×g for 20 min. The pellet wasresuspended in the homogenizing buffer and rehomogenized. The resultinghomogenate was centrifuged at 45,000×g for 20 min. The pellet wasresuspended in 50 mM Tris buffer (pH 7.4 at 4° C.), aliquoted, frozen,and stored at −80° C. for further use.

The membranes were thawed at room temperature and diluted in assaybuffer (50 mM Tris buffer at pH 4) at 37° C. and homogenized using thePolytron tissue disrupter. The membranes were incubated with theradioligand ([³H]prazosin, NEN, 0.1-0.5 nM) and test compound at 37° C.for 30 min. The membranes were then filtered overpolyethyleneimine-treated GF/B unifilter plates using a PackardFiltermate Harvester and washed with ice-cold 50 mM Tris-HCl, 1 mM EDTAbuffer (3×3 sec. washes). Scintillation cocktail was added to the filterplates and bound radioligand determined by liquid scintillationspectrophotometry.

For each experiment, total binding (in the absence of any test orreference compounds) and non-specific binding (10 μM phentolamine) weredetermined. For each sample tested, the concentration producing 50%inhibition of binding (IC₅₀) and Hill Slope (n_(H)) was determined usingiterative non-linear curve fitting techniques with Kaleidagraph (SynergySoftware) or other appropriate software. If the radioligand K_(D) wasknown, the inhibition dissociation constant (K_(I)) of each ligand wasdetermined according to the method of Cheng and Prusoff (Cheng, Y-C. andPrusoff, W. H., Biochem. Pharmacol., 1973, 22, 3099-3108).

Proceeding as in Example L-2, compounds of Formula I were tested andfound to be selective alpha1A/B-adrenoceptor antagonists.

Example L-3 Dog In Vivo Intraurethral and Blood Pressure Assay

The following describes an in vivo assay for measuring the relativeeffect of test compounds on hypogastric nerve stimulation-inducedincreases in intraurethral pressure and phenylephrine-induced increasesin diastolic blood pressure in anesthetized dog.

Male Mongrel dogs (10 to 20 kg) were fasted for 12 to 18 hours andanesthetized with phenobarbital sodium (36 mg/kg, i.v.). An endotrachealtube was inserted and thereafter the lungs were mechanically ventilatedwith room air. The right femoral vein was isolated and cannulated withtwo polyethylene cannulae, one for the administration of a continuousinfusion of phenobarbital sodium (5 to 10 mg/kg/hr) and the other forbolus administration of test substances. The right femoral artery wasisolated and cannulated to the abdominal aorta with a fluid filledpolyethylene cannula connected to an external pressure transducer formonitoring diastolic aortic pressure (DAP). The bladder was exposed viaa ventral midline abdominal incision and emptied of urine through a 22gauge needle. The bladder was cannulated through a stab incision with awater filled balloon catheter connected to an external pressuretransducer for monitoring prostatic intraurethral pressure (IUP). Theright hypogastric nerve (HGN) was carefully isolated and attached to aDastre's electrode for nerve stimulation.

The preparation was allowed to stabilize for at least 20-30 minutes andmust have had a stable basal IUP for not less than 15 minutes prior tocommencement of the assay protocol. The HGN was stimulated (20-50V, 10Hz, 10 msec pulse train for 10 sec) to induce a measurable increase inIUP and then phenylephrine (PE) was administered by bolus injection (6μg/kg, i.v.) to induce a measurable increase in DAP. The HGN stimulationand PE bolus injection were repeated every 5 minutes until threeconsecutive reproducible increases in IUP and DAP were achieved. Testcompound was administered and 10 minutes later the HGN stimulation andPE bolus injection were repeated. Test compound was administeredapproximately every 20 minutes, increasing the dose until maximal ornear maximal inhibition of the increases in IUP and DAP is attained.

Proceeding as in Example L-3, compounds of Formula I were tested andfound to selectively inhibit the HGN stimulation-induced increases inIUP. In contrast, prazosin inhibited increases in IUP and DAP in similarfashion.

Compounds of formula I are active in the above assays. For someexemplary compounds the following table shows corresponding data. pKiCompound alpha 1A alpha 1B alpha 1DN′-{3-[(6,7-dimethoxy-5-methyl-4-oxo-1,4-dihydro- 8.13 9.05 7.16quinazolin-2-ylamino)-methyl]-phenyl}-N,N-di- methyl-acetamidine2-{[4-(2,3-dihydroxy-propoxy)-benzyl]-methyl- 8.15 8.16 6.10amino}-6,7-dimethoxy-5-methyl-1H-quinazolin-4- one2-{[3-(4,5-dihydro-oxazol-2-yl)-benzyl]-methyl- 6.09 7.83 5.58amino}-5,6,7-trimethoxy-1H-quinazolin-4-one2-({4-[(ethyl-methyl-amino)-methyl]-benzyl}- 8.50 8.51 6.26methyl-amino)-5,6,7-trimethoxy-1H-quinazolin-4- one5,6,7-trimethoxy-2-{[3-(3-methoxy-pyrrolidin-1- 8.27 8.13 5.27ylmethyl)-benzyl]-methyl-amino}-1H-quinazolin-4- one6,7-Dimethoxy-5-methyl-2-[methyl-(2-methyl-2,3- 8.49 7.83 5.58dihydro-1H-isoindol-5-ylmethyl)-amino]-1H- quinazolin-4-one2-{[3-(1-Dimethylamino-ethyl)-benzyl]-methyl- 8.81 8.43 6.85amino}-5,6,7-trimethoxy-1H-quinazolin-4-one

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1-48. (canceled)
 49. A compound according to Formula (I),

wherein: Y is C₁₋₄alkylene or C₂₋₄alkenylene; Z is —C(═O)—; R and R′ arealkyl; R⁵ is selected from halogen, cyano, hydroxy, —R⁶ and —OR⁶; R⁶ isselected from alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; R¹⁰is selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl and aralkyl;Ar is

R⁷ is selected from:

R³⁰ and R³¹ each independently is selected from hydrogen, methyl, ethyl,methoxyethyl and hydroxyethyl; and R³² is hydrogen, methyl or ethyl. 50.A compound according to Formula (I),

wherein: Y is C₁₋₄alkylene or C₂₋₄alkenylene; Z is —C(═O)—; R and R′ arealkyl; R⁵ is selected from halogen, cyano, hydroxy, —R⁶ and —OR⁶; R⁶ isselected from alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; R¹⁰is selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl and aralkyl;Ar is;

R⁷ is selected from:

each R³³ independently is hydrogen or alkyl; each R³⁴ independently ishydrogen, alkyl, hydroxy or alkoxy; each R³⁵ independently is hydroxy oralkoxy; and E is (C═O) or CH₂.
 51. A compound according to Formula (I),

wherein: Y is C₁₋₄alkylene or C₂₋₄alkenylene; Z is —C(═O)—; R and R′ arealkyl; R⁵ is selected from halogen, cyano, hydroxy, —R⁶ and —OR⁶; R⁶ isselected from alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; R¹⁰is selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl and aralkyl;Ar is;

R⁸ is selected from:

R³⁰ and R³¹ each independently is selected from hydrogen, methyl, ethyl,methoxyethyl and hydroxyethyl; and R³² is hydrogen, methyl or ethyl. 52.A compound according to Formula (I),

wherein: Y is C₁₋₄alkylene or C₂₋₄alkenylene; Z is —C(═O)—; R and R′ arealkyl; R⁵ is selected from halogen, cyano, hydroxy, —R⁶ and —OR⁶; R⁶ isselected from alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; R¹⁰is selected from hydrogen, alkyl, hydroxyalkyl, aminoalkyl and aralkyl;Ar is

R⁸ is selected from:

each R³³ independently is hydrogen or alkyl; each R³⁴ independently ishydrogen, alkyl, hydroxy or alkoxy; each R³⁵ independently is hydroxy oralkoxy; and E is (C═O) or CH₂.